325 results on '"L. Kangas"'
Search Results
152. 225 Sensitivity of the squamous cell carcinomas of the female genital tract to chemotherapy as assayed by the subrenal capsule method in mice
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L. Kangas, Matti Grönroos, and J. Mäenpää
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Female circumcision ,Pathology ,medicine.medical_specialty ,Chemotherapy ,Endocrinology ,medicine.anatomical_structure ,business.industry ,medicine.medical_treatment ,Cell ,Medicine ,Capsule ,business ,Biochemistry - Published
- 1983
153. Chemotherapy and collagen matrix in tumour transplants
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Frej Stenbäck, L. Kangas, and V-M. Wasenius
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Matrix (mathematics) ,Chemotherapy ,Oncology ,Chemistry ,medicine.medical_treatment ,Cancer research ,medicine - Published
- 1987
154. Long-term exposures to low concentrations of source-specific air pollution, road-traffic noise, and systemic inflammation and cardiovascular disease biomarkers.
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Allaouat S, Yli-Tuomi T, Tiittanen P, Kukkonen J, Kangas L, Mikkonen S, Ngandu T, Jousilahti P, Siponen T, Zeller T, and Lanki T
- Abstract
Objectives: Air pollution and traffic noise are detrimental to cardiovascular health. However, the effects of different sources of these exposures on cardiovascular biomarkers remain unclear. We explored the associations of long-term exposure to source-specific air pollution (vehicular exhausts and residential woodsmoke) at low concentrations and road-traffic noise with systemic inflammation and cardiovascular disease biomarkers., Material and Methods: Modeled outdoor exposure to fine particulate matter (aerodynamic diameter ≤2.5 μm; PM
2.5 ) from vehicular exhausts and residential woodsmoke, nitrogen dioxide (NO2 ) from road traffic, and road-traffic noise were linked to the home addresses of the participants (Finnish residents aged 25-74) in the FINRISK study 1997-2012. The participants were located in the cities of Helsinki, Vantaa, and the region of Turku, Finland. The outcomes were high-sensitivity C-reactive protein (CRP), a biomarker for systemic inflammation, and cardiovascular disease biomarkers N-terminal pro-B-type natriuretic peptide (NT-proBNP) and troponin I. We performed cross-sectional analyses with linear and additive models and adjusted for potential confounders., Results: We found no association between PM2.5 from vehicular exhausts (% CRP difference for 1 μg/m3 increase in PM2.5 : -0.9, 95% confidence interval, CI: -7.2, 5.8), or from residential woodsmoke (% difference: -8.1, 95% CI: -21.7, 7.9) and CRP (N = 4147). Road-traffic noise >70 dB tended to be positively associated with CRP (% CRP difference versus noise reference category of ≤45 dB: 18.3, 95% CI: -0.5, 40.6), but the association lacked significance and robustness (N = 7142). Otherwise, we found no association between road-traffic noise and CRP, nor between NO2 from road traffic and NT-proBNP (N = 1907) or troponin I (N = 1951)., Conclusion: Long-term exposures to source-specific, fairly low-level air pollution from vehicular exhausts and residential woodsmoke, or road-traffic noise were not associated with systemic inflammation and cardiovascular disease biomarkers in this urban area., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Tanja Zeller has patent #397 WO2022043229A1 licensed to a computing device to estimate the probability of myocardial infarction. Tanja Zeller is shareholder of the ART.EMIS GmbH Hamburg. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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155. Hyperspectral imaging to accurately segment skin erythema and hyperpigmentation in cutaneous chronic graft-versus-host disease.
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Saknite I, Kwun S, Zhang K, Hood A, Chen F, Kangas L, Kortteisto P, Kukkonen A, Spigulis J, and Tkaczyk ER
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- Humans, Hyperspectral Imaging, Skin diagnostic imaging, Erythema, Bronchiolitis Obliterans Syndrome, Hyperpigmentation diagnostic imaging, Hyperpigmentation etiology
- Abstract
In 51 lesions from 15 patients with the inflammatory skin condition chronic graft-versus-host-disease, hyperspectral imaging accurately delineated active erythema and post-inflammatory hyperpigmentation. The method was validated by dermatologist-approved confident delineations of only definitely affected and definitely unaffected areas in photographs. A prototype hyperspectral imaging system acquired a 2.5 × 3.5 cm
2 area of skin at 120 wavelengths in the 450-850 nm range. Unsupervised extraction of unknown absorbers by endmember analysis achieved a comparable accuracy to that of supervised extraction of known absorbers (melanin, hemoglobin) by chromophore mapping: 0.78 (IQR: 0.39-0.85) vs. 0.83 (0.53-0.91) to delineate erythema and 0.74 (0.57-0.87) vs. 0.73 (0.52-0.84) to delineate hyperpigmentation. Both algorithms achieved higher specificity than sensitivity. Whereas a trained human confidently marked a median of 7% of image pixels, unsupervised and supervised algorithms delineated a median of 14% and 27% pixels. Hyperspectral imaging could overcome a fundamental practice gap of distinguishing active from inactive manifestations of inflammatory skin disease., (© 2023 Wiley-VCH GmbH.)- Published
- 2023
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156. The Food and Drug Administration's (FDA's) Drug Safety Surveillance During the COVID-19 Pandemic.
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Diak IL, Swank K, McCartan K, Beganovic M, Kidd J, Gada N, Kapoor R, Wolf L, Kangas L, Wyeth J, Salvatore T, Fanari M, LeBoeuf AA, Mishra P, Blum MD, and Dal Pan G
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- Humans, United States epidemiology, Pharmaceutical Preparations, Pandemics, United States Food and Drug Administration, Pharmacovigilance, COVID-19, Poisons
- Abstract
Introduction: On 4 February, 2020, the Secretary of the Department of Health and Human Services declared a public health emergency related to coronavirus disease 2019 (COVID-19), and on 27 March, 2020 declared circumstances existed to justify the authorization of the emergency use of drug and biological products (hereafter, "drugs") for COVID-19. At the outset of the pandemic with uncertainty relating to the virus, many drugs were being used to treat or prevent COVID-19, resulting in the US Food and Drug Administration's (FDA's) need to initiate heightened surveillance across these drugs., Objective: We aimed to describe the FDA's approach to monitoring the safety of drugs to treat or prevent COVID-19 across multiple data sources and the subsequent actions taken by the FDA to protect public health., Methods: The FDA conducted surveillance of adverse event and medication error data using the FDA Adverse Event Reporting System, biomedical literature, FDA-American College of Medical Toxicology COVID-19 Toxicology Investigators Consortium Pharmacovigilance Project Sub-registry, and the American Association of Poison Control Centers National Poison Data System., Results: From 4 February, 2020, through 31 January, 2022, we identified 22,944 unique adverse event cases worldwide and 1052 unique medication error cases domestically with drugs to treat or prevent COVID-19. These were from the FDA Adverse Event Reporting System (22,219), biomedical literature (1107), FDA-American College of Medical Toxicology COVID-19 Toxicology Investigator's Consortium Sub-registry (638), and the National Poison Data System (32), resulting in the detection of several important safety issues., Conclusions: Safety surveillance using near real-time data was critical during the COVID-19 pandemic because the FDA monitored an unprecedented number of drugs to treat or prevent COVID-19. Additionally, the pandemic prompted the FDA to accelerate innovation, forging new collaborations and leveraging data sources to conduct safety surveillance to respond to the pandemic., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
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- 2023
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157. Long-term exposure to ambient fine particulate matter originating from traffic and residential wood combustion and the prevalence of depression.
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Allaouat S, Yli-Tuomi T, Tiittanen P, Turunen AW, Siponen T, Kukkonen J, Kangas L, Kauhaniemi M, Aarnio M, Ngandu T, and Lanki T
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- Cross-Sectional Studies, Depression epidemiology, Environmental Exposure adverse effects, Environmental Exposure analysis, Humans, Particulate Matter adverse effects, Particulate Matter analysis, Prevalence, Wood chemistry, Air Pollutants adverse effects, Air Pollutants analysis, Air Pollution adverse effects, Air Pollution analysis
- Abstract
Introduction: Air pollution has been suggested to be associated with depression. However, current evidence is conflicting, and no study has considered different sources of ambient particulate matter with an aerodynamic diameter below 2.5 µm (PM
2.5 ). We evaluated the associations of long-term exposure to PM2.5 from road traffic and residential wood combustion with the prevalence of depression in the Helsinki region, Finland., Methods: We conducted a cross-sectional analysis based on the Helsinki Capital Region Environmental Health Survey 2015-2016 (N=5895). Modelled long-term outdoor concentrations of PM2.5 were evaluated using high-resolution emission and dispersion modelling on an urban scale and linked to the home addresses of study participants. The outcome was self-reported doctor-diagnosed or treated depression. We applied logistic regression and calculated the OR for 1 μg/m3 increase in PM2.5 , with 95% CI. Models were adjusted for potential confounders, including traffic noise and urban green space., Results: Of the participants, 377 reported to have been diagnosed or treated for depression by a doctor. Long-term exposure to PM2.5 from road traffic (OR=1.23, 95% CI 0.86 to 1.73; n=5895) or residential wood combustion (OR=0.78, 95% CI 0.43 to 1.41; n=5895) was not associated with the prevalence of depression. The estimates for PM2.5 from road traffic were elevated, but statistically non-significant, for non-smokers (OR=1.38, 95% CI 0.94 to 2.01; n=4716)., Conclusions: We found no convincing evidence of an effect of long-term exposure to PM2.5 from road traffic or residential wood combustion on depression., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2021
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158. Heterogeneous Urban Exposures and Prevalent Hypertension in the Helsinki Capital Region, Finland.
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Okokon EO, Yli-Tuomi T, Siponen T, Tiittanen P, Turunen AW, Kangas L, Karppinen A, Kukkonen J, and Lanki T
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- Environmental Exposure analysis, Finland epidemiology, Humans, Particulate Matter analysis, Air Pollutants analysis, Air Pollution analysis, Hypertension epidemiology, Hypertension etiology
- Abstract
Urban dwellers are simultaneously exposed to several environmental health risk factors. This study aimed to examine the relationship between long-term exposure to fine particulate matter (PM
2.5 , diameter < 2.5 µm) of residential-wood-burning and road-traffic origin, road-traffic noise, green space around participants' homes, and hypertension. In 2015 and 2016, we conducted a survey of residents of the Helsinki Capital Region to determine their perceptions of environmental quality and safety, lifestyles, and health statuses. Recent antihypertensive medication was used as an indicator of current hypertensive illness. Individual-level exposure was estimated by linking residential coordinates with modelled outdoor levels of wood-smoke- and traffic-related PM2.5 , road-traffic noise, and coverage of natural spaces. Relationships between exposure and hypertension were modelled using multi-exposure and single-exposure binary logistic regression while taking smooth functions into account. Twenty-eight percent of the participants were current users of antihypertensive medication. The odds ratios (95% confidence interval) for antihypertensive use were 1.12 (0.78-1.57); 0.97 (0.76-1.26); 0.98 (0.93-1.04) and 0.99 (0.94-1.04) for wood-smoke PM2.5 , road-traffic PM2.5 , road-traffic noise, and coverage of green space, respectively. We found no evidence of an effect of the investigated urban exposures on prevalent hypertension in the Helsinki Capital Region.- Published
- 2021
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159. Minimally invasive surgery and transsulcal parafascicular approach in the evacuation of intracerebral haemorrhage.
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Marenco-Hillembrand L, Suarez-Meade P, Ruiz Garcia H, Murguia-Fuentes R, Middlebrooks EH, Kangas L, Freeman WD, and Chaichana KL
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- Cerebral Hemorrhage diagnostic imaging, Cerebral Hemorrhage mortality, Cerebral Hemorrhage physiopathology, Cerebrovascular Circulation, Clinical Decision-Making, Humans, Minimally Invasive Surgical Procedures, Risk Assessment, Risk Factors, Treatment Outcome, Cerebral Hemorrhage surgery, Drainage adverse effects, Drainage instrumentation, Drainage mortality, Neurosurgical Procedures adverse effects, Neurosurgical Procedures instrumentation, Neurosurgical Procedures mortality
- Abstract
Intracerebral haemorrhage (ICH) describes haemorrhage into the brain parenchyma that may result in a decline of the patient's neurological function. ICH is a common cause of morbidity and mortality worldwide. Aggressive surgical treatment for ICH has remained controversial as clinical trials have failed to demonstrate substantial improvement in patient outcome and mortality. Recently, promising mechanical and pharmacological minimally invasive surgery (MIS) techniques for the treatment of ICH have been described. MIS was designed with the objective of reducing morbidity due to complications of surgical manipulation. Mechanical MIS includes the use of tubular retractors and small diameter instruments for ICH removal. Pharmacological methods consist of catheter placement inside the haematoma cavity for the passive drainage of the haematoma over the course of several days. One of the most favourable approaches for MIS is the use of natural corridors for reaching the lesion, such as the transsulcal parafascicular approach. This approach provides an anatomical dissection of the subjacent white matter tracts, causing the least amount of damage while evacuating the haematoma. A detailed description of the currently known MIS techniques and devices is presented in this review. Special attention is given to the transsulcal parafascicular approach, which has particular benefits to provide a less traumatic MIS with promising overall patient outcome., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2019
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160. Residential Wood Combustion in Finland: PM 2.5 Emissions and Health Impacts with and without Abatement Measures.
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Savolahti M, Lehtomäki H, Karvosenoja N, Paunu VV, Korhonen A, Kukkonen J, Kupiainen K, Kangas L, Karppinen A, and Hänninen O
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- Air Pollutants analysis, Air Pollution statistics & numerical data, Environmental Exposure statistics & numerical data, Finland, Humans, Air Pollutants adverse effects, Air Pollution analysis, Environmental Monitoring methods, Particulate Matter adverse effects, Particulate Matter analysis, Wood adverse effects, Wood chemistry
- Abstract
Exposure to fine particles in ambient air has been estimated to be one of the leading environmental health risks in Finland. Residential wood combustion is the largest domestic source of fine particles, and there is increasing political interest in finding feasible measures to reduce those emissions. In this paper, we present the PM
2.5 emissions from residential wood combustion in Finland, as well as the resulting concentrations. We used population-weighed concentrations in a 250 x 250 m grid as population exposure estimates, with which we calculated the disease burden of the emissions. Compared to a projected baseline scenario, we studied the effect of chosen reduction measures in several abatement scenarios. In 2015, the resulting annual average concentrations were between 0.5 and 2 µg/m3 in the proximity of most cities, and disease burden attributable to residential wood combustion was estimated to be 3400 disability-adjusted life years (DALY) and 200 deaths. Disease burden decreased by 8% in the 2030 baseline scenario and by an additional 63% in the maximum feasible reduction scenario. Informational campaigns and improvement of the sauna stove stock were assessed to be the most feasible abatement measures to be implemented in national air quality policies., Competing Interests: The authors declare no conflict of interest.- Published
- 2019
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161. SERMs Promote Anti-Inflammatory Signaling and Phenotype of CD14+ Cells.
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Polari L, Wiklund A, Sousa S, Kangas L, Linnanen T, Härkönen P, and Määttä J
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- Adult, Cell Line, Cell Line, Tumor, Cells, Cultured, Humans, Macrophages drug effects, Middle Aged, NF-kappa B drug effects, Raloxifene Hydrochloride pharmacology, Th2 Cells, Young Adult, Inflammation drug therapy, Lipopolysaccharide Receptors analysis, Selective Estrogen Receptor Modulators pharmacology, Signal Transduction drug effects
- Abstract
Signaling via estrogen receptors (ER) is recognized as an essential part of the immune regulation, and ER-mediated signaling is involved in autoimmune reactions. Especially ERα activation in immune cells has been suggested to skew cytokine production toward Th2/M2-type mediators, which can have protective effect on inflammatory diseases and reduce Th1 and Th17 responses. These effects are caused by increased alternative activation of macrophages and changes in the activation of different T cell populations. In humans, hormonal status has been shown to have a major impact on several inflammatory diseases. Selective estrogen receptor modulators (SERMs) are ER ligands that regulate ER actions in a tissue-specific manner mostly lacking the adverse effects of steroid hormones. The impact of SERMs on the immune system is less studied, but it is suggested that certain SERMs may also produce immunoprotective effects. Here, we show that two novel SERMs and raloxifene affect immune cells by promoting M2 macrophage phenotype, alleviating NFκB activity, inhibiting T cell proliferation, and stimulating the production of anti-inflammatory compounds such as IL10 and IL1 receptor antagonist. Thus, these compounds have high potency as drug candidates against autoimmune diseases.
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- 2018
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162. Effects of ospemifene, a novel selective estrogen-receptor modulator, on human breast tissue ex vivo.
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Eigeliene N, Kangas L, Hellmer C, Kauko T, Erkkola R, and Härkönen P
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- Aged, Apolipoproteins D metabolism, Apoptosis drug effects, Breast metabolism, Breast pathology, Cell Proliferation drug effects, Estrogen Receptor alpha genetics, Estrogen Receptor alpha metabolism, Female, Humans, Middle Aged, Polymorphism, Genetic, Raloxifene Hydrochloride pharmacology, Receptors, Androgen metabolism, Tamoxifen pharmacology, Trefoil Factor-1 metabolism, Breast drug effects, Postmenopause drug effects, Selective Estrogen Receptor Modulators pharmacology, Tamoxifen analogs & derivatives
- Abstract
Objective: Ospemifene (Osp) is a novel selective estrogen-receptor modulator (SERM) accepted for the treatment of dyspareunia, a symptom of postmenopausal vulvovaginal atrophy. We aimed to analyze the effects of Osp on human breast tissue (HBT), in comparison with the clinically established SERMs raloxifene (Ral) and tamoxifen (Tam), using ex vivo explant cultures., Methods: HBT samples were obtained from postmenopausal women undergoing mammoplasty and cultured with or without Osp, Ral, Tam, or 17β-estradiol (E2) for 7 and 14 days, and studied for morphology, proliferation, and apoptosis. The expression of epithelial markers, the estrogen-receptor alpha (ERα), the androgen receptor (AR), TFF1, and apolipoprotein D was evaluated using immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. The PvuII polymorphism of ERS1 was determined., Results: Osp, similar to Ral and Tam, decreased the number of proliferating cells in a concentration-dependent manner (at 100 nM, P < 0.01) and strongly opposed 10 nM E2-stimulated proliferation (P < 0.001). Corresponding effects were observed in the proportions of cells expressing ERα and TFF1 (P < 0.001). At 14 days apoptosis was increased by 100 nM SERMs (P < 0.01), but, notably, decreased by 1 nM Osp and Ral at day 7 (P < 0.05). The SERMs exerted ER-agonist effects on AR-positive cell populations at 1 nM (P < 0.05), but not at 100 nM concentrations. The effects on proliferation and ERα expressing cell numbers were associated with the ERS1 PvuII genotype., Conclusions: In summary, Osp inhibited proliferation and opposed E2 stimulation in normal HBT in an efficacious, but less potent way than Ral and Tam. The ESR1 PvuII polymorphisms may influence the responsiveness of HBT to E2 and SERMs.
- Published
- 2016
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163. Comparing land use regression and dispersion modelling to assess residential exposure to ambient air pollution for epidemiological studies.
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de Hoogh K, Korek M, Vienneau D, Keuken M, Kukkonen J, Nieuwenhuijsen MJ, Badaloni C, Beelen R, Bolignano A, Cesaroni G, Pradas MC, Cyrys J, Douros J, Eeftens M, Forastiere F, Forsberg B, Fuks K, Gehring U, Gryparis A, Gulliver J, Hansell AL, Hoffmann B, Johansson C, Jonkers S, Kangas L, Katsouyanni K, Künzli N, Lanki T, Memmesheimer M, Moussiopoulos N, Modig L, Pershagen G, Probst-Hensch N, Schindler C, Schikowski T, Sugiri D, Teixidó O, Tsai MY, Yli-Tuomi T, Brunekreef B, Hoek G, and Bellander T
- Subjects
- Epidemiologic Studies, Female, Humans, Least-Squares Analysis, Models, Theoretical, Air Pollutants analysis, Air Pollution, Environmental Exposure
- Abstract
Background: Land-use regression (LUR) and dispersion models (DM) are commonly used for estimating individual air pollution exposure in population studies. Few comparisons have however been made of the performance of these methods., Objectives: Within the European Study of Cohorts for Air Pollution Effects (ESCAPE) we explored the differences between LUR and DM estimates for NO2, PM10 and PM2.5., Methods: The ESCAPE study developed LUR models for outdoor air pollution levels based on a harmonised monitoring campaign. In thirteen ESCAPE study areas we further applied dispersion models. We compared LUR and DM estimates at the residential addresses of participants in 13 cohorts for NO2; 7 for PM10 and 4 for PM2.5. Additionally, we compared the DM estimates with measured concentrations at the 20-40 ESCAPE monitoring sites in each area., Results: The median Pearson R (range) correlation coefficients between LUR and DM estimates for the annual average concentrations of NO2, PM10 and PM2.5 were 0.75 (0.19-0.89), 0.39 (0.23-0.66) and 0.29 (0.22-0.81) for 112,971 (13 study areas), 69,591 (7) and 28,519 (4) addresses respectively. The median Pearson R correlation coefficients (range) between DM estimates and ESCAPE measurements were of 0.74 (0.09-0.86) for NO2; 0.58 (0.36-0.88) for PM10 and 0.58 (0.39-0.66) for PM2.5., Conclusions: LUR and dispersion model estimates correlated on average well for NO2 but only moderately for PM10 and PM2.5, with large variability across areas. DM predicted a moderate to large proportion of the measured variation for NO2 but less for PM10 and PM2.5., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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164. Effects of ospemifene on breast tissue morphology and proliferation: a comparative study versus other selective estrogen receptor modulators in ovariectomized rats.
- Author
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Kangas L, Härkönen P, Väänänen K, Keskitalo J, and Eigéliené N
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- Animals, Female, Mammary Glands, Animal anatomy & histology, Ovariectomy, Rats, Rats, Sprague-Dawley, Tamoxifen pharmacology, Cell Proliferation drug effects, Estrogen Antagonists pharmacology, Mammary Glands, Animal drug effects, Mammary Glands, Animal physiology, Selective Estrogen Receptor Modulators pharmacology, Tamoxifen analogs & derivatives
- Abstract
Ospemifene is a tissue-selective estrogen agonist/antagonist that was recently approved for the treatment of dyspareunia associated with vulvar and vaginal atrophy, which occurs in up to approximately 50% of postmenopausal women. The current analyses were conducted to determine whether ospemifene exhibits estrogenic activity in the mammary glands of ovariectomized rats and to compare potential estrogenic activity with selective estrogen receptor modulators (tamoxifen, raloxifene, and toremifene). Three separate studies with differing durations (6, 9, and 28 days) were conducted using similar procedures in ovariectomized Sprague-Dawley rats. Estradiol treatment and sham-treated ovariectomized rats were used as positive and negative controls, respectively. Cell proliferation was examined using labeled 5-bromo-2-deoxyuridine; cytoplasmic prolactin was characterized with antibody staining. The morphology of the mammary gland was studied by histological staining of sections from the right fourth mammary glands, and the excised gland from the left side was used for counting the lobulus number. Neither ospemifene nor selective estrogen receptor modulators substantially induced 5-bromo-2-deoxyuridine staining, altered the morphology of the mammary glands, or changed prolactin immunostaining in ovariectomized rats compared with the ovariectomized controls. With the exception of toremifene, the selective estrogen receptor modulators did not cause a substantial induction in mammary gland lobuli. Estradiol had effects opposite to those of the selective estrogen receptor modulators in these studies. Ospemifene exhibited no substantial estrogenic activity in the mammary gland of ovariectomized rats. Activity in the mammary gland of ovariectomized rats with ospemifene was comparable to raloxifene and tamoxifen., (© Georg Thieme Verlag KG Stuttgart · New York.)
- Published
- 2014
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165. Photosynthetic traits of Sphagnum and feather moss species in undrained, drained and rewetted boreal spruce swamp forests.
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Kangas L, Maanavilja L, Hájek T, Juurola E, Chimner RA, Mehtätalo L, and Tuittila ES
- Abstract
In restored peatlands, recovery of carbon assimilation by peat-forming plants is a prerequisite for the recovery of ecosystem functioning. Restoration by rewetting may affect moss photosynthesis and respiration directly and/or through species successional turnover. To quantify the importance of the direct effects and the effects mediated by species change in boreal spruce swamp forests, we used a dual approach: (i) we measured successional changes in moss communities at 36 sites (nine undrained, nine drained, 18 rewetted) and (ii) photosynthetic properties of the dominant Sphagnum and feather mosses at nine of these sites (three undrained, three drained, three rewetted). Drainage and rewetting affected moss carbon assimilation mainly through species successional turnover. The species differed along a light-adaptation gradient, which separated shade-adapted feather mosses from Sphagnum mosses and Sphagnum girgensohnii from other Sphagna, and a productivity and moisture gradient, which separated Sphagnum riparium and Sphagnum girgensohnii from the less productive S. angustifolium, S. magellanicum and S. russowii. Undrained and drained sites harbored conservative, low-production species: hummock-Sphagna and feather mosses, respectively. Ditch creation and rewetting produced niches for species with opportunistic strategies and high carbon assimilation. The direct effects also caused higher photosynthetic productivity in ditches and in rewetted sites than in undrained and drained main sites.
- Published
- 2014
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166. Effects of the selective estrogen receptor modulator ospemifene on bone in rats.
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Kangas L, Härkönen P, Väänänen K, and Peng Z
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- Animals, Biomechanical Phenomena drug effects, Body Weight drug effects, Bone Density drug effects, Bone Remodeling drug effects, Bone and Bones anatomy & histology, Cell Count, Compressive Strength drug effects, Female, Femur anatomy & histology, Femur drug effects, Femur physiology, Lumbar Vertebrae anatomy & histology, Lumbar Vertebrae drug effects, Lumbar Vertebrae physiology, Luteinizing Hormone blood, Organ Size drug effects, Osteoclasts cytology, Osteoclasts drug effects, Ovariectomy, Rats, Rats, Sprague-Dawley, Tamoxifen pharmacology, Tibia anatomy & histology, Tibia drug effects, Tibia physiology, Uterus drug effects, Uterus metabolism, Bone and Bones drug effects, Bone and Bones physiology, Selective Estrogen Receptor Modulators pharmacology, Tamoxifen analogs & derivatives
- Abstract
Ospemifene is a non-estrogen agent that exerts tissue-specific estrogen agonistic and weak antagonistic effects (i. e., is a selective estrogen receptor modulator [SERM]). The effects of various once-daily oral doses of ospemifene on bone are examined across 3 studies for 4 or 52 weeks after surgery in the ovariectomized (OVX) rat model of postmenopausal bone loss. Ospemifene treatment reduced the loss of bone mineral content and density observed in untreated OVX rats, significantly increased distal femur bone mineral content at 51 weeks at 25 mg/kg dose compared with untreated OVX rats (p<0.01), and significantly increased trabecular bone mineral density of the distal femur and proximal tibia with 1, 5, or 25 mg/kg doses after 52 weeks. Ospemifene 5 and 25 mg/kg preserved distal femur trabecular structure; trabecular number was significantly increased, whereas trabecular separation and eroded surface values were significantly decreased (all p<0.01). Structural changes associated with ospemifene were accompanied by increased mechanical strength of femurs and 4th lumbar vertebra compared with untreated OVX rats. Ospemifene 10 mg/kg prevented OVX-induced bone loss; trabecular bone volume of distal femurs was increased after 4 weeks. Further, histomorphometric measures revealed decreased bone resorption after 4 weeks of ospemifene treatment, with effects similar to other SERMs (raloxifene and droloxifene). Ospemifene 3 and 10 mg/kg significantly inhibited OVX-induced increases in osteoclast number, and doses ≥0.3 mg/kg dose-dependently reversed the OVX-induced increase in the double-labeled volume:bone volume ratio. These results demonstrate antiresorptive, selective agonist effects of ospemifene on bone that appear similar to raloxifene in this in vivo animal model of estrogen deficiency., (© Georg Thieme Verlag KG Stuttgart · New York.)
- Published
- 2014
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167. Tissue selectivity of ospemifene: pharmacologic profile and clinical implications.
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Kangas L and Unkila M
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- Animals, Bone Resorption prevention & control, Bone and Bones drug effects, Bone and Bones pathology, Epithelium drug effects, Epithelium pathology, Female, Humans, Mammary Glands, Human drug effects, Mammary Glands, Human pathology, Organ Specificity, Selective Estrogen Receptor Modulators adverse effects, Selective Estrogen Receptor Modulators therapeutic use, Tamoxifen adverse effects, Tamoxifen pharmacology, Tamoxifen therapeutic use, Vagina drug effects, Vagina pathology, Estrogen Replacement Therapy, Selective Estrogen Receptor Modulators pharmacology, Tamoxifen analogs & derivatives
- Abstract
The multifactorial consequences of menopausal estrogen deficiency affect numerous tissues throughout the body. Supplemental hormonal therapies carry the burden of a risk/benefit ratio that must be highly individualized. Selective estrogen receptor modulators (SERMs) are estrogen receptor (ER) agonist/antagonists designed to induce benefits comparable with estrogen while minimizing adverse effects. Here, we review the estrogen agonist/antagonist profile of ospemifene, a novel triphenylethylene derivative recently approved to treat dyspareunia, a symptom of vulvar and vaginal atrophy (VVA) due to menopause, both preclinically and clinically. Ospemifene binds ERα and ERβ with approximately equal affinities. In preclinical models, ospemifene increased vaginal and uterine epithelial thickness and mucification to the same extent as estrogen. Ospemifene did not induce endometrial hyperplasia in animal models; there also was no stimulatory effect on endometrial cells. In rat and human mammary cells in vitro, ospemifene evokes a dose-dependent inhibition on estrogen-induced cell responses and cell proliferation, supporting an antiestrogenic effect in breast. In contrast, ospemifene has an estrogenic effect on bone, as seen by improved bone mineral density, strength, mass, and histomorphometry in preclinical models, consistent with improvements in markers of bone resorption and formation in postmenopausal women. Based on the preclinical evidence, ospemifene has beneficial estrogen-like effects on the vaginal epithelium, preliminary evidence to support a neutral endometrial profile, antiproliferative effects in breast, and estrogenic effects in bone. Taken together, especially regarding estrogen-like effects on the vaginal epithelium, ospemifene presents a profile of tissue-specific effects that appear novel among available SERMs and well-suited for the treatment of VVA., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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168. Peptide orientation affects selectivity in ion-exchange chromatography.
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Alpert AJ, Petritis K, Kangas L, Smith RD, Mechtler K, Mitulović G, Mohammed S, and Heck AJ
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- Amino Acid Sequence, Cell Line, Humans, Lysine metabolism, Molecular Sequence Data, Peptides chemistry, Peptides metabolism, Phosphates metabolism, Trypsin metabolism, Chromatography, Ion Exchange methods, Peptides isolation & purification
- Abstract
Here we demonstrate that separation of proteolytic peptides, having the same net charge and one basic residue, is affected by their specific orientation toward the stationary phase in ion-exchange chromatography. In electrostatic repulsion-hydrophilic interaction chromatography (ERLIC) with an anion-exchange material, the C-terminus of the peptides is, on average, oriented toward the stationary phase. In cation exchange, the average peptide orientation is the opposite. Data with synthetic peptides, serving as orientation probes, indicate that in tryptic/Lys-C peptides the C-terminal carboxyl group appears to be in a zwitterionic bond with the side chain of the C-terminal Lys/Arg residue. In effect, the side chain is then less basic than the N-terminus, accounting for the specific orientation of tryptic and Lys-C peptides. Analyses of larger sets of peptides, generated from lysates by either Lys-N, Lys-C, or trypsin, reveal that specific peptide orientation affects the ability of charged side chains, such as phosphate residues, to influence retention. Phosphorylated residues that are remote in the sequence from the binding site affect retention less than those that are closer. When a peptide contains multiple charged sites, then orientation is observed to be less rigid and retention tends to be governed by the peptide's net charge rather than its sequence. These general observations could be of value in confirming a peptide's identification and, in particular, phosphosite assignments in proteomics analyses. More generally, orientation accounts for the ability of chromatography to separate peptides of the same composition but different sequence.
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- 2010
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169. Estrogen and the selective estrogen receptor modulator (SERM) protection against cell death in estrogen receptor alpha and beta expressing U2OS cells.
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Kallio A, Guo T, Lamminen E, Seppänen J, Kangas L, Väänänen HK, and Härkönen P
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- Cell Line, Tumor, Cell Survival drug effects, Estradiol metabolism, Estradiol pharmacology, Estrogen Receptor alpha genetics, Estrogen Receptor beta genetics, Etoposide pharmacology, Humans, Interleukin-6 metabolism, Osteoblasts pathology, Raloxifene Hydrochloride metabolism, Raloxifene Hydrochloride pharmacology, Selective Estrogen Receptor Modulators metabolism, Selective Estrogen Receptor Modulators pharmacology, Tamoxifen analogs & derivatives, Tamoxifen metabolism, Tamoxifen pharmacology, Apoptosis drug effects, Estrogen Receptor alpha biosynthesis, Estrogen Receptor beta biosynthesis, Osteoblasts drug effects, Osteoblasts metabolism
- Abstract
In the current work, we compared the ability of 17beta-estradiol (E2) and the selective estrogen receptor modulators (SERMs), tamoxifen (Tam), raloxifene (Ral) and ospemifene (Osp) to promote the survival of osteoblast-derived cells against etoposide-induced apoptosis. In order to compare the roles of the two estrogen receptor (ER) isotypes, we created a U2OS human osteosarcoma cell line stably expressing either ERalpha (ERalpha) or ERbeta (ERbeta). Transfection with either of the ERs was able to render the U2OS cells sensitive to E2. We show that E2 opposed etoposide-induced apoptosis and that the effect was mediated via both ER isotypes. The ER isotype selective agonists propyl-pyrazole-triol (PPT) and diarylpropionitrile (DPN) had the same effect in U2OS/ERalpha and U2OS/ERbeta cells, respectively. Osp also opposed apoptosis at least in U2OS/ERalpha cells. Tam and Ral were not able to protect against etoposide-induced cell death. In order to evaluate the protective effects of E2 and Osp upon etoposide challenge, we studied the expression of two E2-regulated, osteoblast-produced cytokines, IL-6 and OPG in E2 and SERM-treated U2OS/ERalpha and U2OS/ERbeta cells. Etoposide strongly increased expression of IL-6 and decreased that of OPG. E2 opposed IL-6 increase only in U2OS/ERalpha cells and OPG decrease primarily in ERbeta cells. Osp opposed the effect of etoposide on OPG primarily in U2OS/ERbeta cells but interestingly, it had little effect on IL-6 expression. E2, PPT, DNP and Osp also inhibited etoposide-induced death and cytokine changes in SAOS-2 osteosarcoma cells expressing endogenous ERalpha and ERbeta. Collectively, our results suggest that the osteoblast protective anti-apoptotic effects of E2 are mediated by both ERalpha and ERbeta but those of Osp primarily by ERalpha. In addition, E2 and Osp opposed the etoposide-induced increase of IL-6 and decrease of OPG which changes would increase osteoclastic activity. These anti-resorptive effects of E2 and Osp upon etoposide challenge differed from each other and they seemed to be differentially mediated in ERalpha and ERbeta expressing osteoblast-derived U2OS cells.
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- 2008
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170. Differential effects of selective oestrogen receptor modulators (SERMs) tamoxifen, ospemifene and raloxifene on human osteoclasts in vitro.
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Michael H, Härkönen PL, Kangas L, Väänänen HK, and Hentunen TA
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- Animals, Apoptosis drug effects, Bone Resorption prevention & control, Cattle, Cell Differentiation drug effects, Cell Line, Tumor, Cells, Cultured, Coculture Techniques, Dexamethasone pharmacology, Dose-Response Relationship, Drug, Estradiol analogs & derivatives, Estradiol pharmacology, Estrogen Antagonists pharmacology, Fulvestrant, Humans, Lipopolysaccharide Receptors analysis, Macrophage Colony-Stimulating Factor pharmacology, Monocytes cytology, Monocytes drug effects, Monocytes metabolism, Osteoclasts cytology, Osteoclasts metabolism, Osteoprotegerin biosynthesis, RANK Ligand pharmacology, Time Factors, Tumor Necrosis Factor-alpha pharmacology, Osteoclasts drug effects, Raloxifene Hydrochloride pharmacology, Selective Estrogen Receptor Modulators pharmacology, Tamoxifen analogs & derivatives, Tamoxifen pharmacology
- Abstract
Background and Purpose: Several selective oestrogen receptor modulators (SERMs) with oestrogen agonist effects in bone cells and without increased risk of breast and endometrial cancer have been developed. Here, we have investigated the effects of different types of SERMs on osteoclast differentiation, bone resorption and apoptosis in vitro., Experimental Approach: Human peripheral blood-derived CD14+ monocytes were cultured on bovine bone slices in the presence of RANKL, M-CSF, TNF-alpha and dexamethasone for seven days. Also, CD14+ monocytes were co-cultured either with human SaOS-2 or MG-63 osteosarcoma cells, in the presence of parathyroid hormone. Osteoclast cultures were treated with different SERMs. TRACP+ multinucleated cells and C-terminal telopeptide of type I collagen were used as markers for osteoclast formation and bone resorption, respectively., Key Results: In CD14+ monocyte cultures, tamoxifen directly inhibited human osteoclast formation and bone resorption, while raloxifene and ospemifene had no inhibitory effect. In the co-cultures either with SaOS-2 or MG-63 cells, ospemifene and raloxifene as well as tamoxifen inhibited osteoclast formation in a concentration-dependent manner. The inhibitory effect was associated with an increased production of osteoprotegerin. The anti-oestrogen ICI 182 780 completely reversed the effects of these SERMs., Conclusion and Implications: Tamoxifen had an oestrogen receptor dependent, direct, inhibitory effect on human osteoclast differentiation and bone resorption, whereas ospemifene and raloxifene required osteoblastic cells to achieve a similar inhibition. The effects of ospemifene and raloxifene were mediated by oestrogen receptors by a mechanism involving paracrine induction of osteoprotegerin in cultures with osteoblast derived osteosarcoma cells.
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- 2007
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171. Estrogen receptor alpha genotype confers interindividual variability of response to estrogen and testosterone in mesenchymal-stem-cell-derived osteoblasts.
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Leskelä HV, Olkku A, Lehtonen S, Mahonen A, Koivunen J, Turpeinen M, Uusitalo J, Pelkonen O, Kangas L, Selander K, and Lehenkari P
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- 17-Hydroxysteroid Dehydrogenases metabolism, Adult, Aged, Aged, 80 and over, Aromatase metabolism, Cell Differentiation drug effects, Cells, Cultured, Estrogen Receptor alpha metabolism, Female, Gene Frequency, Genotype, Humans, Male, Mesenchymal Stem Cells metabolism, Middle Aged, Osteoblasts cytology, Osteoblasts metabolism, Osteogenesis drug effects, Polymorphism, Restriction Fragment Length, Estrogen Receptor alpha genetics, Estrogens pharmacology, Mesenchymal Stem Cells cytology, Osteoblasts drug effects, Testosterone pharmacology
- Abstract
Hormone replacement therapy is effectively used to prevent postmenopausal bone loss. Variation in response to the therapy is, however, frequently seen. In addition, the direct effects of sex steroids on isolated human bone marrow stromal cells have been reported to vary depending on the donor, but the biological mechanisms are not understood. The aim of this study was to investigate the effects of 17beta-estradiol (E2) and testosterone in human-bone-marrow-derived mesenchymal stem cell (MSC) cultures from both female and male donors of various ages. The osteoblast differentiation capacity and activity of the MSCs were quantified in vitro by measuring alkaline phosphatase activity and calcium deposition. We show here that also the osteoblast responses of MSCs to sex hormones vary widely depending on the donor. When the results from all donors were analyzed together, treatment with E2 increased calcium deposition significantly by MSCs of both sexes but ALP activity only in the male MSCs. Testosterone had no effect on ALP activity nor calcium deposition in either sex. To further characterize the individual variation, we investigated estrogen receptor alpha PvuII restriction site polymorphism with PCR. Restriction fragment-length polymorphism was assigned as P or non-P, P signifying the absence of the restriction site. Our results indicate that higher basal osteoblast differentiation capacity of MSCs is associated with the presence of the P allele in females, whereas higher response to sex steroids treatment is associated with the non-P allele. These results could help explain the contradictory effects of E2 on osteoblasts in vitro and might also provide new insights to understanding the differences in responses to hormone replacement therapy.
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- 2006
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172. New inhibitors of 17beta-hydroxysteroid dehydrogenase type 1.
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Messinger J, Hirvelä L, Husen B, Kangas L, Koskimies P, Pentikäinen O, Saarenketo P, and Thole H
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- Crystallography, X-Ray, Enzyme Inhibitors chemical synthesis, Humans, Inhibitory Concentration 50, Molecular Structure, Protein Conformation, Structure-Activity Relationship, Computer-Aided Design, Drug Design, Enzyme Inhibitors chemistry, Estradiol Dehydrogenases antagonists & inhibitors, Pyrimidinones chemistry
- Abstract
The estradiol-synthesizing enzyme 17beta-hydroxysteroid dehydrogenase type 1 (17betaHSD1) is mainly responsible for the conversion of estrone (E1) to the potent estrogen estradiol (E2). It is a key player to control tissue levels of E2 and is therefore an attractive target in estradiol-dependent diseases like breast cancer or endometriosis. We selected a unique non-steroidal pyrimidinone core to start a lead optimization program. We optimized this core by modulation of R1-R6. Its binding mode at the substrate-binding site of 17betaHSD1 is complex and difficult to predict. Nevertheless, some basic structure-activity relationships could be identified. In vitro, the most active pyrimidinone derivative showed effective inhibition of recombinant human 17betaHSD1 at nanomolar concentrations. In intact cells overexpressing the human enzyme, IC50 values in the lower micromolar range were determined. Furthermore, the pyrimidinone proved its use in vivo by significantly reducing 17betaHSD1-dependent tumor growth in a new nude mouse model.
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- 2006
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173. Evaluation of inhibitors for 17beta-hydroxysteroid dehydrogenase type 1 in vivo in immunodeficient mice inoculated with MCF-7 cells stably expressing the recombinant human enzyme.
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Husen B, Huhtinen K, Poutanen M, Kangas L, Messinger J, and Thole H
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- 17-Hydroxysteroid Dehydrogenases genetics, Animals, Breast Neoplasms genetics, Cell Line, Tumor, Dose-Response Relationship, Drug, Estradiol Dehydrogenases genetics, Female, Humans, Mice, Mice, Inbred Strains, Recombinant Proteins antagonists & inhibitors, Xenograft Model Antitumor Assays, 17-Hydroxysteroid Dehydrogenases antagonists & inhibitors, Antineoplastic Agents pharmacology, Breast Neoplasms enzymology, Enzyme Inhibitors pharmacology, Estradiol Dehydrogenases antagonists & inhibitors, Estrone pharmacology
- Abstract
17Beta-hydroxysteroid dehydrogenase (17HSD1) is an enzyme activating estrone (E1) to estradiol (E2). In the present study, a mechanistic animal model was set up for evaluating putative inhibitors for the human enzyme in vivo. Estrogen-dependent MCF-7 human breast carcinoma cells were stably transfected with a plasmid expressing human 17HSD1. These cells formed estrogen-dependent tumors in immunodeficient mice. In the optimized model, tumor sizes were decreased in both ovariectomized and intact vehicle-treated mice, whereas they were maintained or slightly increased in mice supplemented 2 weeks with an appropriate dose of the 17HSD1-substrate E1. Tumor sizes in mice treated with 0.1 micromol/kg/d of E1 were reduced by administering 5 micromol/kg/d of different 17HSD1-inhibitors and a 86% reduction in size was detected with the most potent inhibitor. A dose-response relationship in the inhibitory effect of this compound further confirmed the validity of the model for testing the drug candidates in vivo.
- Published
- 2006
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174. Selective estrogen receptor modulators prevent neointima formation after vascular injury.
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Savolainen-Peltonen H, Luoto NM, Kangas L, and Häyry P
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- Animals, Aorta injuries, Cell Proliferation drug effects, Cells, Cultured, Endothelium, Vascular cytology, Estradiol pharmacology, Estrogens pharmacology, Female, Fulvestrant, Muscle, Smooth, Vascular cytology, Muscle, Smooth, Vascular metabolism, Ovariectomy, Raloxifene Hydrochloride pharmacology, Rats, Rats, Wistar, Tamoxifen pharmacology, Tunica Intima drug effects, Tunica Intima pathology, Aorta drug effects, Endothelium, Vascular drug effects, Endothelium, Vascular injuries, Estradiol analogs & derivatives, Muscle, Smooth, Vascular drug effects, Selective Estrogen Receptor Modulators pharmacology, Tamoxifen analogs & derivatives
- Abstract
Exploitation of estrogen's vasculoprotective properties in drug design is difficult due to its adverse effects on endometrium and breast. Selective estrogen receptor modulators (SERM) act as estrogen agonists in some tissues but are anti-estrogenic in others. We investigate here whether tamoxifen, raloxifene, and two novel SERMs, ospemifene and fispemifene, preserve estrogen's beneficial effects on the ovariectomized rat vascular wall, and correlate their effects with natural estrogen (17beta-E2) and a pure anti-estrogen ICI 182,780. All compounds dose-dependently (0.0025-25 mg/kg/day) inhibited neointimal thickening at 7 days after aorta denudation injury. At 28 days, tamoxifen and ospemifene (2.5 mg/kg/day) reduced intimal nuclei number and intimal area equal to 17beta-E2, while raloxifene and fispemifene had no effect. Replacing the drug at 14 days with vehicle did not induce any rebound effect at 28 days, and furthermore, resulted in a smaller neointima with raloxifene and fispemifene. 17beta-E2 and the SERMs also significantly enhanced reendothelialization. All compounds inhibited replication and all but fispemifene inhibited migration of vascular SMC and cells from cultured aortic explants in vitro. Finally, only 17beta-E2 increased the weight of the uterus above that of normal rats. Interestingly, ICI 182,780 also weakly inhibited neointima formation and SMC proliferation at 7 days, suggesting that non-estrogen receptor mediated effects may have also played a role. In conclusion, SERMs have beneficial estrogen agonist effects in the injured vascular wall through their regulation of vascular SMC function and reendothelialization. Early intervention is of particular importance in preventing the injury-response.
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- 2004
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175. Comparative study of the short-term effects of a novel selective estrogen receptor modulator, ospemifene, and raloxifene and tamoxifen on rat uterus.
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Zheng H, Kangas L, and Härkönen PL
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- Animals, Base Sequence, DNA Primers, DNA Replication, Female, Gene Expression Regulation drug effects, Genes, fos, Organ Size drug effects, Polymerase Chain Reaction, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Tamoxifen analogs & derivatives, Uterus metabolism, Vascular Endothelial Growth Factor A genetics, Estrogen Receptor Modulators pharmacology, Raloxifene Hydrochloride pharmacology, Tamoxifen pharmacology, Uterus drug effects
- Abstract
To investigate the differential short-term effects of selective estrogen receptor (ER) modulators (SERMs) on uterus, we treated adult ovariectomized rats with a novel SERM, ospemifene (Osp), two previously established SERMs (tamoxifen and raloxifene (Ral)) and estradiol. The expression of two estrogen-regulated early response genes c-fos and vascular endothelial growth factor (VEGF), and DNA synthesis were analysed at 1-24 h after treatment of ovariectomized rats. Induction of c-fos mRNA by each of the SERMs showed a biphasic pattern with peaks at 3 and 20 h, respectively. The maximum level of VEGF mRNA was observed at 1 h after raloxifene and 6 h after tamoxifen or ospemifene treatment. Maximum levels of the c-fos and VEGF mRNA after raloxifene treatment were higher than those seen after treatments with E2 or a corresponding dose of tamoxifen or ospemifene. DNA synthesis was significantly increased by ospemifene, tamoxifen and raloxifene both in luminal and glandular epithelium. The stimulation was transient, peaking at 16 h. In comparison, the maximum level observed at 16 h after E2 treatment sustained at least until 24 h. DNA synthesis in stromal cells was increased by the SERMs but not by E2 at 24 h. When treated together with E2, the SERMs were able to antagonise E2-stimulated DNA synthesis at 16 h. Our results demonstrate that the initial response of uterus to ospemifene, raloxifene and tamoxifen includes activation of early response genes and even transient stimulation of DNA synthesis in spite of their different long-term effects. However, the early stimulatory events may be mediated by different mechanisms leading to diverging pathways in various tissue compartments and development of differential SERM-specific long-term responses of uterus.
- Published
- 2004
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176. Effects of ospemifene (FC-1271a) on uterine endometrium, vaginal maturation index, and hormonal status in healthy postmenopausal women.
- Author
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Voipio SK, Komi J, Kangas L, Halonen K, DeGregorio MW, and Erkkola RU
- Subjects
- Administration, Oral, Aged, Dose-Response Relationship, Drug, Double-Blind Method, Endometrium pathology, Estradiol blood, Female, Follicle Stimulating Hormone blood, Hot Flashes drug therapy, Hot Flashes pathology, Humans, Luteinizing Hormone blood, Luteinizing Hormone drug effects, Middle Aged, Pain Measurement, Parathyroid Hormone blood, Postmenopause, Prolactin blood, Prolactin drug effects, Reference Values, Sex Hormone-Binding Globulin drug effects, Tamoxifen administration & dosage, Tamoxifen therapeutic use, Ultrasonography, Vagina diagnostic imaging, Endometrium drug effects, Hormones blood, Tamoxifen analogs & derivatives, Tamoxifen pharmacology, Vagina drug effects
- Abstract
Objective: Selective estrogen receptor modulators (SERMs) are drugs that exhibit both estrogen agonistic and antagonistic effects that are tissue-specific. Ospemifene (FC-1271a) is a novel SERM compound, which has been shown in animal models to have estrogen-like effects on bone and the cardiovascular system, while having antiestrogen-like effects in uterus and breast. In this study, we investigated the effects of ospemifene on the uterine endometrium, vaginal maturation index and hormonal status in healthy postmenopausal women., Methods: The study was conducted as a double-blind, placebo-controlled phase I study, where 40 healthy postmenopausal women volunteers were randomized to receive daily oral doses of ospemifene either 25, 50, 100 or 200 mg or placebo for 12 weeks. Vaginal ultrasonography and endometrial biopsy were performed and vaginal maturation index determined at baseline and at 12 weeks' visit. Serum concentrations of estradiol, luteinizing hormone, follicle stimulating hormone (FSH), sex-hormone binding globulin (SHBG), parathyroid hormone and prolactin were determined from samples taken at baseline, at 4 days and at 4, 12, and 16 weeks' visits. Climacteric symptoms were assessed using 12 visual analogue scales (VAS) at baseline and at the end of the study., Results: No clinically significant changes were seen in endometrial thickness at any dose level. Ospemifene exerted a very weak estrogenic effect on endometrial histology. On the other hand, it induced a clear estrogenic effect on vaginal epithelium. Among the endocrine parameters only FSH and SHBG showed significant dose dependent changes; FSH decreased and SHBG increased during the treatment. In general, ospemifene was well tolerated. The 25 and 50 mg doses tended to reduce climacteric symptoms, but no statistically significant differences were observed between different doses of ospemifene and placebo. The highest dose level (200 mg) induced more subjective adverse reactions, especially hot flushes, than lower doses., Conclusion: Our study suggests that a safe and well tolerated dose of ospemifene for potential clinical use may be between 25 and 100 mg. Further studies are needed to substantiate the results of this Phase I pilot study.
- Published
- 2002
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177. Antioxidant and antitumor effects of hydroxymatairesinol (HM-3000, HMR), a lignan isolated from the knots of spruce.
- Author
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Kangas L, Saarinen N, Mutanen M, Ahotupa M, Hirsinummi R, Unkila M, Perälä M, Soininen P, Laatikainen R, Korte H, and Santti R
- Subjects
- Animals, Antioxidants pharmacokinetics, Biological Availability, Disease Models, Animal, Female, Lignans pharmacokinetics, Male, Mice, Mice, Inbred C57BL, Random Allocation, Rats, Rats, Sprague-Dawley, Sensitivity and Specificity, Antioxidants pharmacology, Lignans pharmacology, Mammary Neoplasms, Experimental drug therapy, Plant Extracts pharmacology
- Abstract
The antioxidant properties of hydroxymatairesinol (HM-3000) were studied in vitro in lipid peroxidation, superoxide and peroxyl radical scavenging, and LDL-oxidation models in comparison with the known synthetic antioxidants Trolox (a water-soluble vitamin E derivative), butylated hydroxyanisol (BHA) and butylated hydroxytoluene (BHT). On a molar basis HM-3000 was a more effective antioxidant than Trolox in all assays and more effective than BHT or BHA in lipid peroxidation and superoxide scavenging test. The in vivo antioxidative effect (evaluated as the weight gain of C57BL/6J mice fed an alpha-tocopherol-deficient diet) of HM-3000 (500 mg/kg per day) was comparable to that of DL-alpha-tocopherol (766 mg/kg per day). The antitumor activity of HM-3000 was studied in dimethylbenz[a]anthracene (DMBA)-induced rat mammary cancer. HM-3000 had a statistically significant inhibitory effect on tumor growth. Prevention of tumor formation was also evaluated in the Apc(Min) mice model, which develops intestinal polyps spontaneously. HM-3000 was given in diet at 30 mg/kg per day and decreased the formation of polyps and prevented beta-catenin accumulation into the nucleus, the pathophysiological hallmark of polyp formation in this mouse model. In short-term toxicity studies (up to 28 days) HM-3000 was essentially non-toxic when given p.o. to rats and dogs (daily doses up to 2000 and 665 mg/kg, respectively); HM-3000 was shown to be well absorbed (> 50% of the dose) and rapidly eliminated. In human studies HM-3000 has been given in single doses up to 1350 mg to healthy male volunteers without treatment-related adverse events. Rapid absorption from the gastrointestinal tract and partial metabolism to enterolactone in humans was demonstrated. In summary, HM-3000 is a safe, novel enterolactone precursor lignan with antioxidant and antitumor properties.
- Published
- 2002
178. Biocompatibility evaluation of dura mater substitutes in an animal model.
- Author
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Barbolt TA, Odin M, Léger M, Kangas L, Hoiste J, and Liu SH
- Subjects
- Absorbable Implants, Animals, Brain pathology, Dura Mater pathology, Fibrosis, Inflammation, Models, Animal, Polydioxanone, Polyglactin 910, Polytetrafluoroethylene, Rabbits, Tissue Adhesions, Wound Healing, Biocompatible Materials, Brain surgery, Dura Mater surgery
- Abstract
Dura-Guard Dural Repair Patch, PRECLUDE Dura Substitute, and Codman ETHISORB Dura Patch were evaluated in a six-month dural tissue reaction study in rabbits. Bilateral craniotomy was followed by subdural implantation for each dura mater substitute. The surgical procedure for the sham control group was the same except that no material was implanted. Implantation of all of these dura mater substitutes for 28, 91, or 182 days post-implantation did not result in any deaths or clinical neurobehavioral abnormalities, changes in cerebrospinal fluid, or significant macroscopic changes at necropsy. However, histomorphologic evaluation of the implantation sites revealed some differences in the tissue response to these materials. For Dura-Guard Dural Repair Patch, a nonabsorbable material derived from bovine pericardium, the implantation site was characterized by fibrosis of the overlying area with islands of osseous metaplasia and adhesions to the brain surface. Over time, infiltrative fibrosis of the implant resulted in separation of the collagenous layers of the implant and compression of the underlying brain. Fibrosis of the overlying area that incorporated this material formed a 'replacement' dura mater. Adhesions to the brain surface observed initially were still present at six months post-implantation. Implantation of PRECLUDE Dura Substitute, a nonabsorbable material comprised of expanded polytetrafluoroethylene, resulted in virtually no early reaction, and few adhesions to the brain surface at any time period. Although this material was eventually incorporated by fibrosis, islands of osseous metaplasia were also observed in this 'replacement' dura mater. The tissue reaction to Codman ETHISORB Dura Patch, an absorbable material comprised of polyglactin 910 and polydioxanone, was generally characterized by low-grade granulomatous inflammation and initial adhesions to the brain surface. The three-dimensional structure of this implant acted as a scaffold to guide the development and integration of a 'replacement' dura mater. The absorption of the material was associated with complete resolution of the inflammatory reaction, a lack of cerebral adhesions, and restoration of the normal architecture of this region. In conclusion, subdural implantation of Dura-Guard Dural Repair Patch, PRECLUDE Dura Substitute, or Codman ETHISORB Dura Patch in rabbits for up to six months resulted in the eventual restoration of the dura mater without significant adverse effects. However, osseous metaplasia associated with nonabsorbable Dura-Guard Dural Repair Patch and PRECLUDE Dura Substitute, and the infiltration of Dura-Guard Dural Repair Patch by fibrosis suggests that long-term follow-up may be needed after the use of these materials in patients. An advantage of Codman ETHISORB Dura Patch was that it was completely absorbed after guiding the restoration of the dura mater without any morphological sequelae.
- Published
- 2001
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179. Pharmacokinetics of finrozole (MPV-2213ad), a novel selective aromatase inhibitor, in healthy men.
- Author
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Ahokoski O, Irjala K, Taalikka M, Manninen P, Halonen K, Kangas L, Salminen E, Huupponen R, and Scheinin H
- Subjects
- Administration, Oral, Adult, Area Under Curve, Aromatase Inhibitors, Biological Availability, Cross-Over Studies, Dose-Response Relationship, Drug, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors blood, Estradiol metabolism, Humans, Male, Nitriles administration & dosage, Nitriles blood, Solutions, Tablets, Triazoles administration & dosage, Triazoles blood, Enzyme Inhibitors pharmacokinetics, Nitriles pharmacokinetics, Triazoles pharmacokinetics
- Abstract
Aims: To investigate the pharmacokinetics of finrozole (MPV-2213ad), a novel competitive aromatase enzyme inhibitor, in healthy male volunteers., Methods: The study was an open, partly randomized cross-over study including 23 volunteers receiving single doses of 3, 9 mg or 30 mg of finrozole as tablets or solution with 14 days between the administrations. The highest dose was given as tablets only. Serum concentrations of finrozole were determined using high performance liquid chromatography combined with mass spectrometry., Results: The mean time to peak serum concentration ranged from 2.5 to 3.1, and 0.6-0.7 h after tablets and solution, respectively. The Cmax values increased as the dose increased. The calculated apparent mean elimination half-life (t(1/2,z)) was approximately 3 h after the solution, and approximately 8 h after the tablet. The AUC(0,infinity) after finrozole tablets increased proportionally from 3 mg to 9 mg and from 3 to 30 mg. The calculated relative mean bioavailabilities (AUC(0,infinity)-ratio) for the 3 mg and 9 mg doses of finrozole as tablets were 89% and 78%, respectively., Conclusions: The absorption of finrozole from the tablet formulation was relatively rapid, and the apparent elimination half-life was longer after the tablet than after the solution, probably reflecting overlap of the absorption with the elimination phase.
- Published
- 2001
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180. Pre-clinical subdural tissue reaction and absorption study of absorbable hemostatic devices.
- Author
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Barbolt TA, Odin M, Léger M, and Kangas L
- Subjects
- Animals, Brain drug effects, Brain pathology, Brain physiopathology, Encephalitis pathology, Encephalitis physiopathology, Gelatin Sponge, Absorbable adverse effects, Gelatin Sponge, Absorbable metabolism, Meninges drug effects, Meninges pathology, Meninges physiopathology, Meningitis pathology, Meningitis physiopathology, Neurosurgical Procedures methods, Pilot Projects, Rabbits, Treatment Outcome, Blood Loss, Surgical prevention & control, Encephalitis chemically induced, Meningitis chemically induced, Neurosurgical Procedures instrumentation, Subdural Space surgery
- Abstract
SURGIFOAM (Absorbable Gelatin Sponge, USP), a new absorbable hemostatic sponge, GELFOAM (Absorbable Gelatin Sponge, USP) or Avitene (microfibrillar collagen hemostat) were evaluated in a three-month tissue reaction and absorption study in rabbits. Bilateral craniotomy was followed by subdural implantation of each hemostatic device. A sham control group was treated in a similar way except that no material was implanted. Implantation of these hemostatic devices for 15, 43, or 92 days did not result in any deaths or clinical neurobehavioral abnormalities, changes in cerebrospinal fluid, or significant macroscopic observations at necropsy. The tissue reaction to SURGIFOAM sponge was characterized by transient granulomatous inflammation that was slightly less intense than that observed for GELFOAM sponge which correlated to slightly longer absorption. In contrast, the tissue reaction to Avitene hemostat was characterized by moderate to marked granulomatous inflammation with an acute inflammatory component indicating a greater degree of tissue irritancy. Sequelae of this reaction were still observed at 92 days post-implantation. The tissue reaction in humans to SURGIFOAM sponge used as a hemostatic agent for neurologic surgical procedures is expected to be comparable to that observed with GELFOAM sponge, resulting in no significant adverse reactions for patients. This animal model was useful to assess the tissue reaction and absorption of biomaterials implanted in contact with the central nervous system, and it was able to differentiate between materials of biologic origin.
- Published
- 2001
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181. Selective estrogenic effects of a novel triphenylethylene compound, FC1271a, on bone, cholesterol level, and reproductive tissues in intact and ovariectomized rats.
- Author
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Qu Q, Zheng H, Dahllund J, Laine A, Cockcroft N, Peng Z, Koskinen M, Hemminki K, Kangas L, Väänänen K, and Härkönen P
- Subjects
- 9,10-Dimethyl-1,2-benzanthracene, Animals, Bone and Bones drug effects, Breast Neoplasms drug therapy, Cholesterol blood, Estrogen Antagonists therapeutic use, Female, Humans, Mammary Neoplasms, Experimental chemically induced, Mammary Neoplasms, Experimental pathology, Mice, Mice, Nude, Organ Size drug effects, Raloxifene Hydrochloride pharmacology, Rats, Rats, Sprague-Dawley, Reference Values, Tamoxifen pharmacology, Tamoxifen therapeutic use, Toremifene pharmacology, Transplantation, Heterologous, Tumor Cells, Cultured, Uterus drug effects, Uterus physiology, Bone and Bones physiology, Breast Neoplasms pathology, Estrogen Antagonists pharmacology, Mammary Neoplasms, Experimental prevention & control, Osteoporosis prevention & control, Ovariectomy, Tamoxifen analogs & derivatives
- Abstract
FC1271a is a novel triphenylethylene compound with a tissue-selective profile of estrogen agonistic and weak antagonistic effects. It specifically binds to the estrogen receptor alpha and beta with affinity closely similar to that of toremifene and tamoxifen. To study the in vivo effects of the compound, 4-month-old rats were sham operated (sham) or ovariectomized (OVX) and treated daily for 4 weeks with various doses of FC1271a or vehicle (orally). FC1271a was able to oppose OVX-induced bone loss by maintaining the trabecular bone volume of the distal femur. Accordingly, the OVX-induced loss of bone strength was prevented at doses of 1 and 10 mg/kg. FC1271a also prevented the OVX-induced increase in serum cholesterol in a dose-dependent manner. No significant changes in uterine wet weight or morphology were observed in the OVX-rats treated with 0.1 or 1 mg/kg FC1271a, but at a dose of 10 mg/kg it had a slightly estrogenic effect. In immature rats the effect of FC1271a on uterine wet weight was less stimulatory than that of toremifene or tamoxifen, but more stimulatory than that of raloxifene or droloxifene. The appearance of the dimethylbenzanthracene (DMBA)-induced mammary tumors was inhibited by treatment of DMBA-treated rats with FC1271a in a dose-dependent manner. In human MCF-7 breast cancer cell tumors raised in nude mice in the presence of estrogen, the growth and expression of pS2 marker gene could not be maintained after estrogen withdrawal by treatment with FC1271a. No formation of DNA adducts was observed in the liver of the FC1271a-treated rats. In conclusion, the bone-sparing, antitumor, and cholesterol-lowering effects of FC1271a combined with a low uterotropic activity and lack of liver toxicity indicate that FC1271a could be an important alternative in planning antiosteoporosis therapy for estrogen deficiency.
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- 2000
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182. Hydroxymatairesinol, a novel enterolactone precursor with antitumor properties from coniferous tree (Picea abies).
- Author
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Saarinen NM, Wärri A, Mäkelä SI, Eckerman C, Reunanen M, Ahotupa M, Salmi SM, Franke AA, Kangas L, and Santti R
- Subjects
- 4-Butyrolactone analogs & derivatives, 4-Butyrolactone urine, Administration, Oral, Animals, Antineoplastic Agents, Phytogenic chemistry, Antineoplastic Agents, Phytogenic pharmacology, Antineoplastic Agents, Phytogenic therapeutic use, Disease Models, Animal, Female, Furans metabolism, Genitalia, Male drug effects, Genitalia, Male growth & development, Lignans chemistry, Lignans pharmacology, Lignans therapeutic use, Lignans urine, Male, Phytotherapy, Rats, Rats, Sprague-Dawley, Receptors, Estrogen metabolism, Uterus drug effects, Uterus growth & development, Antineoplastic Agents, Phytogenic metabolism, Lignans metabolism, Mammary Neoplasms, Experimental drug therapy, Trees chemistry
- Abstract
The potential for the extraction of the plant lignan hydroxymatairesinol (HMR) in large scale from Norway spruce (Picea abies) has given us the opportunity to study the metabolism and biological actions of HMR in animals. HMR, the most abundant single component of spruce lignans, was metabolized to enterolactone (ENL) as the major metabolite in rats after oral administration. The amounts of urinary ENL increased with the dose of HMR (from 3 to 50 mg/kg), and only minor amounts of unmetabolized HMR isomers and other lignans were found in urine. HMR (15 mg/kg body wt po) given for 51 days decreased the number of growing tumors and increased the proportion of regressing and stabilized tumors in the rat dimethylbenz[a]anthracene-induced mammary tumor model. HMR (50 mg/kg body wt) did not exert estrogenic or antiestrogenic activity in the uterine growth test in immature rats. HMR also showed no antiandrogenic responses in the growth of accessory sex glands in adult male rats. Neither ENL nor enterodiol showed estrogenic or antiestrogenic activity via a classical alpha- or beta-type estrogen receptor-mediated pathway in vitro at < 1.0 microM. HMR was an effective antioxidant in vitro.
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- 2000
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183. Renal cell carcinomas and pancreatic adenocarcinomas produce nidogen in vitro and in vivo.
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Oivula J, Lohi J, Tani T, Kangas L, Kiviluoto T, Kivilaakso E, Butkowski R, and Virtanen I
- Subjects
- Animals, Basement Membrane metabolism, Fluorescent Antibody Technique, Humans, Immunoenzyme Techniques, Mice, Mice, Nude, Neoplasm Transplantation, Transplantation, Heterologous, Tumor Cells, Cultured, Adenocarcinoma metabolism, Carcinoma, Renal Cell metabolism, Kidney Neoplasms metabolism, Membrane Glycoproteins biosynthesis, Neoplasm Proteins biosynthesis, Pancreatic Neoplasms metabolism
- Abstract
The production of nidogen by four renal cell carcinoma (RCC) and three pancreatic adenocarcinoma (PAc) cell lines has been studied in cell culture and in xenografted tumours in nude mice. In RCC cells, immunoreactivity for nidogen was seen only after exposure to monensin to induce cytoplasmic accumulation of secretory proteins. In PAc cells, immunoreaction was also detectable in control cells. Immunoblotting of control and monensin-exposed cells and immunoprecipitation of culture media of radioactively labelled cells demonstrated the production of nidogen polypeptide of Mr ca. 150000 by six of the seven cell lines. Basement membranes (BMs) and stroma of the xenografted tumours derived from these six cell lines demonstrated immunoreactivity for both human and mouse nidogen, as revealed with species-specific antibodies. The ability of the cells to produce nidogen in vitro and deposit in vivo was positively correlated with high histological grade of the xenografted tumours, although the small number of cell lines studied calls for further studies to confirm this. The distribution of nidogen in human RCC and PAc specimens was also studied by immunohistochemistry. There was strong immunoreactivity for nidogen in tumour stroma, BM of carcinoma cell nests, and endothelial basal lamina, but no conclusions could be drawn regarding histological grade and immunostaining patterns, because stromal production could not be ruled out. The results show that nidogen is produced by human carcinoma cells both in vitro and in vivo., (Copyright 1999 John Wiley & Sons, Ltd.)
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- 1999
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184. The effect of toremifene on bone and uterine histology and on bone resorption in ovariectomised rats.
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Karlsson S, Mäntylä E, Hirsimäki Y, Niemi S, Nieminen L, Nieminen K, and Kangas L
- Subjects
- Amino Acids blood, Animals, Biomarkers, Calcium urine, Drug Interactions, Estradiol pharmacology, Female, Hydroxyproline metabolism, In Vitro Techniques, Ovariectomy adverse effects, Random Allocation, Rats, Rats, Sprague-Dawley, Bone Resorption prevention & control, Bone and Bones drug effects, Estrogen Antagonists pharmacology, Toremifene pharmacology, Uterus drug effects
- Abstract
The effect of the selective oestrogen receptor modulator, toremifene, to inhibit ovariectomy-induced bone loss was studied in rats. The oral doses were 0.3, 3.0 or 30 mg/kg/day for 2 months. 17beta-oestradiol (5 microg/kg/day, subcutaneously) was used as positive control. One group was also treated with a combination of 17beta-oestradiol (5 microg/kg) and toremifene (3.0 mg/kg). Biochemical markers were urinary hydroxyproline and calcium (adjusted with urinary creatinine levels) and the serum level of pyridinoline cross-linked carboxy terminal telopeptide, a bone specific collagen breakdown product. The femoral and sternal trabecular bone thickness served as histological parameters. Ovarectomy increased the levels of hydroxyproline and pyrodinoline and decreased the trabecular bone thickness compared to the sham-operated control group. This was inhibited by both test compounds but 17beta-oestradiol was more efficient. Toremifene did not reverse the ovariectomy-induced reduction of urinary calcium but inhibited the 17beta-oestradiol-related increase. When administered together with oestradiol, toremifene did not reverse the positive effect of 17beta-oestradiol on bone, however toremifene reversed the oestradiol-related uterothrophic effects. These findings indicate that the antagonistic features of toremifene dominate in the rat uterus the agonistic properties do in the bone.
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- 1999
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185. The proliferation in uterine compartments of intact rats of two different strains exposed to high doses of tamoxifen or toremifene.
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Karlsson S, Iatropoulos MJ, Williams GM, Kangas L, and Nieminen L
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- Animals, Atrophy chemically induced, Atrophy pathology, Body Weight drug effects, Bromodeoxyuridine analysis, Cell Division drug effects, Diethylstilbestrol toxicity, Endometrium drug effects, Endometrium pathology, Epithelial Cells drug effects, Epithelial Cells pathology, Female, Myometrium drug effects, Myometrium pathology, Proliferating Cell Nuclear Antigen analysis, Rats, Rats, Inbred F344, Rats, Sprague-Dawley, Species Specificity, Stromal Cells drug effects, Stromal Cells pathology, Uterus chemistry, Uterus pathology, Estrogen Antagonists toxicity, Tamoxifen toxicity, Toremifene toxicity, Uterus drug effects
- Abstract
Uterine Cell proliferation was studied in intact Sprague-Dawley (SD) and Fischer 344 (F344) rats exposed to the antiestrogens tamoxifen (TAM; 5, 10, 20, or 40 mg/kg) and toremifene (TOR: 21.2 or 42.4 mg/kg). The antiestrogens were administered to animals via gavage daily for 2 or 12 wk. Uterine proliferation was assessed using markers for the proliferating cell nuclear antigen (PCNA) and by the bromodeoxyuridine (BrdU) method. Diethylstilbestrol (DES) was used as an estrogenic reference compound. The antiestrogens either reduced or prevented changes of myometrial and stromal proliferation indices (PI). TAM and TOR caused a time-dependent reduction of endometrial glands without an associated decrease in cell proliferation. In the luminal columnar epithelium, the antiestrogens depressed PCNA PI but enhanced BrdU PI, indicating a low continuous DNA synthesis in otherwise quiescent cells. The antiestrogens induced focal hyperplastic multilayered epithelia with PCNA-positive basal cells along segments of the luminal uterine epithelium. We suggest that this hyperplastic epithelium represents remnants from the glandular epithelium. DES was less efficient in inducing these changes but induced squamous metaplasias in the F344 rats. Uterine effects of the 2 antiestrogens were comparable with the exception of I TAM-exposed (40 mg/kg) SD rat that showed squamous metaplasia. F344 rats were more sensitive to the estrogenic action of DES than were the SD rats.
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- 1998
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186. Expression of cytochrome P450 genes encoding enzymes active in the metabolism of tamoxifen in human uterine endometrium.
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Hukkanen J, Mäntylä M, Kangas L, Wirta P, Hakkola J, Paakki P, Evisalmi S, Pelkonen O, and Raunio H
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- Adult, Aged, Blotting, Southern, Female, Humans, Middle Aged, RNA, Messenger, Antineoplastic Agents, Hormonal metabolism, Cytochrome P-450 Enzyme System metabolism, Endometrium enzymology, Estrogen Antagonists metabolism, Tamoxifen metabolism
- Abstract
Long-term tamoxifen therapy is associated with increased risk of uterine endometrial cancer and benign alterations. Tamoxifen is metabolized to reactive intermediates by endometrial tissue, and tamoxifen therapy-induced DNA adducts have been found in human endometrium. Since metabolic activation is often catalyzed by cytochrome P450 (CYP) enzymes, the expression profile of individual xenobiotic-metabolizing CYP genes was studied in human uterine endometrium by reverse transcriptase-polymerase chain reaction. The following CYP mRNAs were detected: CYP2B6, CYP2C, CYP2E1, CYP3A4, CYP3A5, CYP4B1, and CYP11A. Amplification of CYP1A1, CYP1A2, CYP2A6, CYP2D6, CYP2F1, CYP3A7, and CYP19 was not found. CYP3A5 and CYP4B1 transcripts were found only in samples from premenopausal women. These data suggest that the human endometrial epithelium has the potential of producing CYP enzymes known to generate genotoxic intermediates from tamoxifen and metabolites that affect oestrogen receptors.
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- 1998
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187. Endocrine mechanism of action of toremifene at the level of the central nervous system in advanced breast cancer patients.
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Számel I, Hindy I, Budai B, Kangas L, Hajba A, and Lammintausta R
- Subjects
- Female, Follicle Stimulating Hormone metabolism, Gonadotropin-Releasing Hormone drug effects, Gonadotropin-Releasing Hormone metabolism, Humans, Ovary metabolism, Postmenopause metabolism, Sex Hormone-Binding Globulin drug effects, Sex Hormone-Binding Globulin metabolism, Thyrotropin-Releasing Hormone drug effects, Thyrotropin-Releasing Hormone metabolism, Antineoplastic Agents, Hormonal pharmacology, Breast Neoplasms metabolism, Hypothalamo-Hypophyseal System drug effects, Ovary drug effects, Toremifene pharmacology
- Abstract
Purpose: To differentiate the antagonistic and agonistic effect of toremifene at the level of the hypothalamus-hypophysis axis a leutinizing hormone-releasing hormone (LHRH) test was performed during a phase II clinical trial., Methods: In 15 postmenopausal patients with advanced breast cancer, follicle-stimulating hormone (FSH) and LH release--induced by an LHRH agonist (Suprefact injection, 0.5 mg s.c.)--was monitored during a 16-week period of toremifene treatment (60 mg/day p.o.). Prolactin, estradiol, and sex hormone-binding globulin (SHBG) levels were also measured. The functional test was carried out prior to toremifene therapy and then 4, 8, 12, and 16 weeks afterward., Results: The drug sensitized the pituitary to the action of the gonadotrophins; the LHRH-induced FSH and LH release showed a considerably increasing tendency during the toremifene therapy. Estradiol levels decreased statistically significantly and SHBG levels showed a statistically significant increase. A decreased level of prolactin is the sign of an antiestrogenic effect of toremifene on the hypophysis and, as a result, provides evidence for a direct influence of toremifene upon the pituitary. An increase in LH and prolactin release in response to the LHRH test was characteristic in the responders., Conclusion: According to the LHRH test, the antagonistic effect of toremifene seems to be more dominant than the concomitantly existing agonistic property. Neither clinical nor endocrinological side effects could be observed at the level of the CNS during a prolonged period of toremifene administration.
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- 1998
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188. Pancreatic carcinomas deposit laminin-5, preferably adhere to laminin-5, and migrate on the newly deposited basement membrane.
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Tani T, Lumme A, Linnala A, Kivilaakso E, Kiviluoto T, Burgeson RE, Kangas L, Leivo I, and Virtanen I
- Subjects
- Adenocarcinoma metabolism, Adenocarcinoma pathology, Animals, Basement Membrane physiology, Carcinoma pathology, Cell Adhesion physiology, Cell Movement physiology, Extracellular Matrix Proteins metabolism, Humans, Integrins metabolism, Mice, Mice, Nude, Neoplasm Transplantation, Pancreatic Ducts, Pancreatic Neoplasms pathology, Physical Stimulation, Transplantation, Heterologous, Tumor Cells, Cultured physiology, Kalinin, Carcinoma metabolism, Cell Adhesion Molecules metabolism, Pancreatic Neoplasms metabolism
- Abstract
We studied the adhesion mechanism of pancreatic carcinoma using in vitro adhesion and migration assays of stable cell lines and tumors grown from these cell lines in nude mice. We also compared the results with the expression profiles of laminins and their receptors in pancreatic carcinomas to evaluate the relevance of these mechanisms in vivo. All of the cell lines preferably adhered to laminin-5, irrespective of their capability to synthesize laminin-5. Cell migration was studied in the presence of hepatocyte growth factor, as it increased the speed of migration manyfold. Herbimycin A treatment and antibodies against the beta 1 and alpha 3 integrin subunits and laminin alpha 3 chain almost entirely blocked cell migration of the BxPC-3 cell line, whereas migration was nearly unaffected by RGD peptide and only moderately inhibited by antibody against the alpha 6 integrin subunit. Indirect immunofluorescence microscopy of wounded BxPC-3 cells suggested a rapid endocytosis of alpha 3 integrin subunit in the cells at the margin of the wound and a rapid, polarized rearrangement of the alpha 6 beta 4 integrin. Especially HGF-treated cultures showed a prominent cytoplasmic reaction for laminin-5 at the margin of the wound. Xenografted cells formed tumors that produced and deposited the same laminin chains as the in vitro cultures. Frozen sections of human pancreatic carcinomas showed reactivity for laminin chains suggestive for expression of laminin-1 and laminin-5. Both xenografted tumors and human pancreatic carcinomas also showed stromal reactivity for laminin-5. Electron microscopy of the human tumors suggested that this was due to an abundant reduplication the basement-membrane-like material around the nests of malignant cells. Our results suggest that pancreatic carcinomas synthesize and deposit laminin-5 in the basement membrane in an abnormal manner. Invading cells adhere to this newly produced basement membrane and migrate on it by using the alpha 3 beta 1 integrin receptor recognizing laminin-5.
- Published
- 1997
189. Combination immunotherapy of the P815 murine mastocytoma with killer cells, IL-2 and anti-estrogens.
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Baral E, Nagy E, Kangas L, and Berczi I
- Subjects
- Animals, Antineoplastic Agents, Hormonal therapeutic use, Combined Modality Therapy, Cytotoxicity, Immunologic, Female, Humans, Immunity, Cellular, Immunotherapy, Killer Cells, Lymphokine-Activated immunology, Mast-Cell Sarcoma drug therapy, Mice, Mice, Inbred DBA, Sarcoma, Experimental drug therapy, Sarcoma, Experimental therapy, T-Lymphocytes, Cytotoxic immunology, Estrogen Antagonists therapeutic use, Interleukin-2 therapeutic use, Mast-Cell Sarcoma therapy, Tamoxifen therapeutic use, Toremifene therapeutic use
- Abstract
Background: Lymphokine activated killer (LAK) cells, cytotoxic T lymphocytes (CTL) and interleukin-2 (IL-2) all are being tested in cancer immunotherapy with modest success. The anti-estrogenic drug, toremifene (T0), was found earlier to amplify cancer immunotherapy with killer cells in mice. Here T0 is examined in combination with CTL and IL-2 in immunotherapy experiments., Materials and Methods: The P815 mastocytoma of DBA/2 mice was treated with combinations of CTL, LAK cells and T0 and combinations of CTL, IL-2 and T0 along with control groups. Tumor growth rate and mortality has been recorded., Results: Combined treatment with CTL and LAK cells cured 25% of tumor bearing animals, as did treatment with tamoxifen (TX) or T0 alone. When killer cells were given in conjunction with anti-estrogens the cure rate was 75% with both TX and T0. Human recombinant IL-2 significantly inhibited tumor growth but no cures occurred. CTL alone cured 25% of the animals. When CTL and IL-2 treatment was given jointly with T0 75% of tumor bearing animals were cured., Conclusions: The results indicate that treatment with anti-estrogens increased the efficiency of immunotherapy by killer cells. This was true also when CTL therapy was supplemented with IL-2 treatment.
- Published
- 1997
190. Combination therapy of the H2712 murine mammary carcinoma with cytotoxic T lymphocytes and anti-estrogens.
- Author
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Baral E, Nagy E, Kangas L, and Berczi I
- Subjects
- Animals, Combined Modality Therapy, Cytotoxicity, Immunologic, Female, Immunotherapy, Interferon-gamma therapeutic use, Mammary Neoplasms, Experimental drug therapy, Mice, Mice, Inbred C3H, Spleen immunology, Survival Analysis, Antineoplastic Agents, Hormonal therapeutic use, Estrogen Antagonists therapeutic use, Mammary Neoplasms, Experimental therapy, T-Lymphocytes, Cytotoxic immunology, Tamoxifen therapeutic use, Toremifene therapeutic use
- Abstract
Background: The triphenylethylene antiestrogenic agents, tamoxifen (TX) and toremifene (TO), are currently being used for the therapy of estrogen dependent breast carcinomas and for some other estrogen receptor positive tumors. Some observations indicate that these drugs may have a beneficial effect on estrogen receptor negative tumors as well., Materials and Methods: The H2712 mammary carcinoma of C3H/HeJ mice was studied in combination immunotherapy experiments using cytotoxic T lymphocytes (CTL) and TX or TO. The effect of TX and TO on the in vitro lysis of H2712 cells by CTL was also investigated. Finally, the H2712 cells were examined for the presence of estrogen receptors., Results: Both TX and TO potentiated the lysis of H2712 cells by CTL in vitro, and exerted a growth inhibitory and therapeutic effect on H2712 mammary carcinomas in vivo. The therapeutic effect of CTL isolated from tumor bearing mice was improved on H2712 carcinomas when the animals were also treated orally by TX or TO. Using the dextran-coated charcoal assay, H2712 cells were found to be negative for classical estrogen receptors., Conclusions: These results indicate that the anti-estrogens, TX and TO, have the ability to suppress the growth of the estrogen receptor negative mammary carcinoma and to amplify target cell lysis by tumor-reactive CTL. By this mechanism these drugs enhance host immunity to an estrogen receptor negative tumor.
- Published
- 1997
191. Antioxidant properties of the triphenylethylene antiestrogen drug toremifene.
- Author
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Ahotupa M, Mäntylä E, and Kangas L
- Subjects
- Animals, Biomarkers blood, Dose-Response Relationship, Drug, Female, In Vitro Techniques, Male, Microsomes, Liver metabolism, Rats, Rats, Sprague-Dawley, Toremifene analogs & derivatives, Antioxidants pharmacology, Estrogen Antagonists pharmacology, Lipid Peroxidation drug effects, Toremifene pharmacology
- Abstract
The aim of the present study was to investigate antioxidativity of the triphenylethylene antiestrogen toremifene. Toremifene and its structural analogues were studied for their ability to inhibit chain reactions of lipid peroxidation and to act as scavengers of free radicals in vitro, and the effects of toremifene were compared to those of the estrogens, tamoxifen and known antioxidants. Moreover, the in vivo antioxidativity of toremifene was tested in a long-term experiment with rats. The ability of toremifene to prevent lipid peroxidation was assayed in two different test systems. In the first assay (initiated with ascorbate/ADP-FeCl3, detection by the formation of TBA-reactive material) toremifene was found to act as an efficient membrane antioxidant with an IC50-value (18 microM) comparable to that of tamoxifen (26 microM) and alpha-tocopherol (43 microM). Toremifene derivatives 4-hydroxytoremifene (IC50 = 8 microM) and Fc 1159 (IC50 = 31 microM), as well as diethylstilbestrol (IC50 = 17 microM) were also active while estradiol showed only weak antioxidativity (IC50 = 300 microM) in this test system. In the other assay (peroxidation initiated with t-butylhydroperoxide, detection by luminol-enhanced chemiluminescence) toremifene prevented lipid peroxidation only at high concentrations (IC50 = 450 microM) but the metabolite 4-hydroxytoremifene (IC50 = 0.18 microM), estradiol (IC50 = 4.6 microM) and diethylstilbestrol (IC50 = 1.7 microM) showed potent antioxidant activity. The potency of 4-hydroxytoremifene even exceded that of alpha-tocopherol (IC50 = 2.0 microM) and butylated hydroxyanisole (IC50 = 1.1 microM). Toremifene was found to have some superoxide anion but no peroxyl radical scavenging activity. Interestingly, diethylstilbestrol turned out to be a potent scavenger of peroxyl radicals. Treatment of female Sprague-Dawley rats with toremifene (12 or 48 mg/kg) was found to decrease serum levels of lipid peroxides. This was seen at various time points (2 days, 5 weeks, 6 and 12 months) during long-term administration of toremifene to rats, and results obtained with two different methods (diene conjugation, TBA-reactive material) gave similar results. The present study thus showed that (i) like steroidal estrogens and tamoxifen toremifene is a potent membrane antioxidant in vitro, (ii) the antioxidant action of toremifene is not due to scavenging of free radicals and, importantly, (iii) toremifene acts antioxidatively also in living organisms in vivo.
- Published
- 1997
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192. A phase III comparison of two toremifene doses to tamoxifen in postmenopausal women with advanced breast cancer. Eastern European Study Group.
- Author
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Gershanovich M, Garin A, Baltina D, Kurvet A, Kangas L, and Ellmén J
- Subjects
- Adult, Aged, Aged, 80 and over, Disease Progression, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Middle Aged, Postmenopause, Quality of Life, Antineoplastic Agents, Hormonal therapeutic use, Breast Neoplasms drug therapy, Estrogen Antagonists therapeutic use, Tamoxifen therapeutic use, Toremifene therapeutic use
- Abstract
Efficacy and safety of toremifene 60 and 240 mg daily (TOR60 and TOR240) are compared to 40 mg tamoxifen daily (TAM40) in postmenopausal women with advanced estrogen receptor (ER) positive or ER unknown breast cancer. The study is randomized and open label in three parallel groups. Primary efficacy variables are response rate and time to progression. WHO and ECOG criteria were used for measurable and nonmeasurable disease assessment, respectively. Safety was reported according to WHO criteria. Altogether 463 patients were randomized (157 to TOR60, 157 to TOR240, and 149 to TAM40). By data cut-off, after 20.5 months median follow-up time, over 70% of the patients had experienced disease progression. Response rates are 20.4%, 28.7%, and 20.8% in TOR60. TOR240, and TAM40, respectively. TOR60 and TAM40 show statistically equivalent efficacy and the difference between TOR240 and TAM40 is not significant (P = 0.112). Median times to progression are 4.9 (TOR60), 6.1 (TOR240), and 5.0 (TAM40) months and the corresponding hazard ratios (TAM:TOR) 1.015 and 1.124. Again, TOR60 and TAM40 are statistically equivalent and the difference between TOR240 and TAM40 is not significant (P = 0.374). All treatments were well tolerated. As a conclusion, TOR60 and TAM40 show equivalent clinical efficacy and tolerability. The higher dose of toremifene slightly but not statistically significantly improves response rate and time to progression. In postmenopausal women, toremifene 60 mg daily is an effective and safe treatment of advanced ER-positive or ER-unknown breast cancer.
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- 1997
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193. Human ornithine decarboxylase-overproducing NIH3T3 cells induce rapidly growing, highly vascularized tumors in nude mice.
- Author
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Auvinen M, Laine A, Paasinen-Sohns A, Kangas A, Kangas L, Saksela O, Andersson LC, and Hölttä E
- Subjects
- 3T3 Cells, Animals, Cattle, Cell Transformation, Neoplastic, Endothelial Growth Factors genetics, Genes, jun, Genes, myc, Genes, p53, Humans, Lymphokines genetics, Membrane Glycoproteins genetics, Mice, Mice, Nude, Neoplasms, Experimental genetics, RNA, Messenger analysis, Thrombospondins, Urokinase-Type Plasminogen Activator genetics, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors, Neoplasms, Experimental etiology, Neovascularization, Pathologic etiology, Ornithine Decarboxylase physiology
- Abstract
Overexpression of human ornithine decarboxylase (ODC) under the control of strong promoters induces morphological transformation of immortalized NIH3T3 and Rat-1 fibroblasts [M. Auvinen et al., Nature (Lond.), 360: 355-358, 1992]. We demonstrate here that ODC-overproducing NIH3T3 cells are tumorigenic in nude mice, giving rise to rapidly growing, large fibrosarcomas at the site of inoculation. The tumors are capable of invading host fat and muscle tissues and are vascularized abundantly. To disclose the molecular mechanism(s) driving the tumorigenic, invasive, and angiogenic phenotype of the tumors, the ODC-overproducing cell lines and tumor tissues were analyzed for the expression of various potential regulators and mediators of cell proliferation, matrix degradation, and angiogenesis. The tumorigenicity of ODC transformants was associated with elevated polyamine levels and down-regulated growth factor receptors. The invasiveness of the ODC-induced tumors could not be attributed to overexpression of various known extracellular matrix-degrading proteases or matrix metalloproteinases. The induction of the tumor neovascularization proved not to be elicited by vascular endothelial growth factor or basic fibroblast growth factor. Instead, the ODC-overexpressing cells appeared to secrete a novel angiogenic factor(s) that was able to promote migration of bovine capillary endothelial cells in collagen gels and increase the proliferation of human endothelial cells in vitro. In parallel, ODC-transformed cells displayed down-regulation of thrombospondin-1 and -2, the negative regulators of angiogenesis. Thus, the induction of the angiogenic phenotype of the ODC transformants is likely due both to increased expression and secretion of the new angiogenesis-stimulating factor(s) and decreased production and release of the antiangiogenic thrombospondins.
- Published
- 1997
194. Expression of type IV collagen alpha1(IV)-alpha6(IV) polypeptides in normal and developing human kidney and in renal cell carcinomas and oncocytomas.
- Author
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Lohi J, Korhonen M, Leivo I, Kangas L, Tani T, Kalluri R, Miner JH, Lehto VP, and Virtanen I
- Subjects
- Adenoma, Oxyphilic metabolism, Adult, Animals, Humans, Immunohistochemistry, Mice, Neoplasm Metastasis, Neoplasm Transplantation, Peptide Fragments metabolism, Transplantation, Heterologous, Carcinoma, Renal Cell metabolism, Collagen metabolism, Kidney embryology, Kidney metabolism, Kidney Neoplasms metabolism
- Abstract
Type IV collagen trimer is a major component of basement membranes (BMs). It is composed of polypeptides named alpha1(IV)-alpha6(IV) chains. Chains alpha1,2(IV) are widely expressed in BMs while alpha3(IV)-alpha6(IV) are more restricted in human tissues. We have now studied by immunohistochemical means the distribution of collagen IV chains in fetal and adult human kidney, in oncocytomas, in renal cell carcinomas (RCCs) and their metastases and in experimental xenografts of human tumors. alpha1,2(IV) chains were found in all BMs of fetal and adult kidney as well as of renal tumors, while alpha3(IV)-alpha6(IV) chains were found in BMs of distal segments of developing and mature tubules. alpha3(IV)-alpha5(IV) chains were seen also in BMs of developing fetal glomeruli after the capillary loop stage. Most of the RCCs and their metastases showed occasional expression of alpha3(IV)-alpha6(IV) with papillary variants showing only expression of alpha5(IV) chain. There was a distinct expression of alpha3(IV)-alpha5(IV) chains in BMs of 3 oncocytomas. In 2 of them a variable expression of the alpha6(IV) chain was seen. In 3 of 4 xenografts, immunoreactivity for human-specific monoclonal antibody (MAb) for alpha1,2(IV) was seen in the BM-like structures. No alpha3-alpha6(IV) was seen in any of the xenografts, while polyclonal antiserum for type IV collagen presented immunoreactivity in BMs of all xenografts. Our results show that oncocytomas and most of the RCCs express scarce variants of type IV collagen containing alpha3(IV)-alpha6(IV) chains. In experimental xenograft tumors, both implanted RCC cells and host stromal cells have a capacity to produce type IV collagen.
- Published
- 1997
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195. Anti-estrogens potentiate the immunotherapy of the P815 murine mastocytoma by cytotoxic T lymphocytes.
- Author
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Nagy E, Baral E, Kangas L, and Berczi I
- Subjects
- Animals, Female, Mice, Mice, Inbred DBA, Adoptive Transfer, Estrogen Antagonists pharmacology, Mast-Cell Sarcoma therapy, T-Lymphocytes, Cytotoxic immunology, Tamoxifen pharmacology, Toremifene pharmacology
- Abstract
Many animal and human tumors are infiltrated with killer cells. Recent studies have shown that the stimulation of such killer cells with interleukin-2 improves their tumor rejecting capacity. In this paper we demonstrate that the anti-estrogens, tamoxifen (TX) and toremifene (TO), enhance host resistance by sensitizing the tumor target to killer cell mediated lysis. The P815 mastocytoma syngeneic to DBA/21 mice was used. Cytotoxic T lymphocytes (CTL) were detected in the spleens of mice 12-14 days after tumor inoculation. In vitro target, effector, or both cell types were treated with either TX (1 microM) or TO (5 microM) for 4 hours prior to cytotoxicity testing by 51Cr release. Mice bearing P815 mastocytomas, 5 mm in diameter, were treated orally with TX or TO and were given CTL isolated from the spleens of tumor bearing donors i.p. Tumor growth, mortality, and immunological memory in cured animals were monitored. Both TX and TO treatment sensitized P815 target cells to lysis by CTL isolated from tumor bearing animals. The transfer of killer cells from the spleens of tumor bearing mice produced tumor suppression in the recipients, which could be enhanced by additional oral treatment by TX or TO. Complete cure was achieved in a significant number of animals, showing partial or complete resistance to a subsequent lethal dose of P815 cells. These experiments indicate that killer cells isolated from mice bearing progressive tumors can have an immunotherapeutic effect in syngeneic tumor bearing recipients and that the antiestrogens, TX and TO, may be used to potentiate the immunotherapy of this tumor.
- Published
- 1997
196. Immunotherapy of the SL2-5 murine lymphoma with natural killer cells and tamoxifen or toremifene.
- Author
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Baral E, Nagy E, Kangas L, and Berczi I
- Subjects
- Animals, Female, Mice, Mice, Inbred DBA, Adoptive Transfer, Antineoplastic Agents, Hormonal therapeutic use, Estrogen Antagonists therapeutic use, Killer Cells, Natural immunology, Lymphoma therapy, Tamoxifen therapeutic use, Toremifene therapeutic use
- Abstract
It is well established that tamoxifen (TX) has a therapeutic effect on estrogen receptor positive tumors by inhibiting the binding of estradiol to its receptor. However, repeated clinical observations indicate that tamoxifen may also have beneficial effects on estrogen receptor negative tumors. In vitro cytotoxicity experiments were performed with the SL2-5 murine lymphoma using interleukin (IL)-2 activated syngeneic NK cells as effectors with or without TX or TO treatment. The effect of TX or TO (10 mg/kg/day/animal in feed) on the immunotherapy of SL2-5 lymphoma with syngeneic IL-2 activated NK cells was also investigated in syngeneic DBA/2 mice. Assays of SL2-5 cells for estrogen and progesterone receptors were also performed. Both TX and TO enhanced significantly the susceptibility of the SL2-5 lymphoma to lysis by IL-2 activated NK cells in vitro. When TX or TO treatment was combined with NK cell immunotherapy of this tumor, both drugs potentiated significantly tumor regression and cure rate when compared to groups receiving NK therapy alone. This tumor does not express classical receptors for estrogens or progesterone. These results indicate that combination treatment with the antiestrogens, TX and TO, acts synergistically with the immunotherapeutic effect of IL-2 activated NK cells in a syngeneic tumor host system.
- Published
- 1997
197. [Results of phase II clinical trial of Tamoxifen and Toremifen in two different doses in advanced breast cancer in postmenopausal women].
- Author
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Gershanovich ML, Garin AM, Baltinia D, Kurvet A, Kangas L, and Ellmen Iu
- Subjects
- Aged, Breast Neoplasms pathology, Disease Progression, Drug Administration Schedule, Female, Humans, Middle Aged, Treatment Outcome, Antineoplastic Agents, Hormonal administration & dosage, Breast Neoplasms drug therapy, Postmenopause, Tamoxifen administration & dosage, Toremifene administration & dosage
- Abstract
Efficacy and safety of toremifene 60 and 240 mg daily (TOR 60 and TOR 240) are compared to 40 mg tamoxifen daily (NFV 40) in postmenopausal women with advanced estrogen receptor (ER) positive of ER unknown breast cancer. The study is randomized in three parallel groups. Primary efficacy variables are response rate and time to progression. WHO and ECOG criteria were used for measurable and nonmeasurable disease assessment, respectively. Safely was reported according to WHO criretia. Altogether 463 patients were randomized (157 to TOR 60, 157 to TOR 240 and 149 to TAM 40). By data cut-off, after 20.5 months medianfollow-up time, over 70% of the patients had experienced disease progression. Response rates are 20.4%, 28.7% in TOR 60, TOR 240 and TAM 40, respectively. TOR 60 and TAM 40 show statistically equivalent efficacy and the difference between TOR 240 and TAM 40 is not significant (P = 0.112). Median times to progression are 4.9 (TOR 60), 6.1 (TOR 240) and 5.0 (TAM 40) months and corresponding hazard ratios (TAM:TOR) 1.015 and 1.124. Again, TOR 60 and TAM 40 are statistically equivalent and the difference between TOR 240 and TAM 40 is not significant (P = 0.374). All treatments were well tolerated. As a conclusion TOR 60 and TAM 40 show equivalent clinical efficacy and tolerability. The higher dose of toremifene slightly but not significantly improved response rate and time to progression. In postmenopausal women, toremifene (60 mg) daily is an effective and safe treatment of advanced ER positive or ER unknown breast cancer.
- Published
- 1997
198. Mitotic index in the subrenal capsule assay as an indicator of the chemosensitivity of ovarian cancer.
- Author
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Suonio E, Lipponen P, Mäenpää J, Syrjänen K, Kangas L, and Tuomisto L
- Subjects
- Animals, Drug Screening Assays, Antitumor, Female, Humans, In Vitro Techniques, Logistic Models, Male, Mice, Mice, Inbred Strains, Neoplasm Transplantation, Prognosis, Adenocarcinoma drug therapy, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Mitotic Index, Ovarian Neoplasms drug therapy, Subrenal Capsule Assay
- Abstract
The subrenal capsule assay (SRCA) is used in clinical oncology to assess the sensitivity of individual malignant tumors to various anticancer agents and their combinations. Mitotic indices reflect cancer cell proliferation and have prognostic value in epithelial neoplasms, including ovarian carcinoma. We combined the two tests (SRCA, mitotic index) by evaluating the numbers of mitotic figures per square millimeter of neoplastic epithelium (M/V) in paraffin-embedded tumor samples after SRCA. The M/V index was compared with the tumor size measurement (dTS), which is used in conventional SRCA to predict the drug response. Histology examination showed insignificant changes in the size of tumor transplants due to host reaction but disclosed a number of potential errors in the use of dTS to evaluate transplant growth and drug effects. In our series of 62 patients with advanced ovarian carcinoma the M/V value was superior to the dTS in explaining the clinical response after 6 months as assessed at second-look laparotomy. Patients showing no response had significantly higher M/V values than did those displaying complete or partial responses (P < 0.033). The use of 6 mitotic figures/mm2 as a limit differentiating responders from nonresponders resulted in an overall predictive accuracy of 79% in the logistic regression analysis. In comparison to the FIGO stage, residual tumor size, and the dTS, the M/V value obtained for the cytostatic combination given to the patient was the single most significant factor predicting the 6-month clinical response. The results indicate that the combined use of the M/V index and SRCA is a promising new approach to prediction of the drug response in ovarian adenocarcinoma.
- Published
- 1997
- Full Text
- View/download PDF
199. Expression of laminin in renal-cell carcinomas, renal-cell carcinoma cell lines and xenografts in nude mice.
- Author
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Lohi J, Tani T, Leivo I, Linnala A, Kangas L, Burgeson RE, Lehto VP, and Virtanen I
- Subjects
- Adenoma, Oxyphilic chemistry, Animals, Antibodies, Monoclonal, Culture Media, Humans, Kidney chemistry, Mice, Mice, Nude, Neoplasm Transplantation, Precipitin Tests, Reference Values, Transplantation, Heterologous, Tumor Cells, Cultured, Carcinoma, Papillary chemistry, Carcinoma, Renal Cell chemistry, Kidney Neoplasms chemistry, Laminin analysis
- Abstract
We studied the expression of laminin (Ln) chains (alpha1-alpha3, beta1-beta3, gamma1) in human renal-cell carcinomas (RCC), papillary renal neoplasms (PRN) and oncocytomas, in RCC cell lines and their xenografts. In RCCs the basement membranes (BM) showed immunoreactivity for chains of Ln-1 (alpha1-beta1-gamma1). Only in well-differentiated RCCs could vessel BMs be distinguished from those of carcinoma cell islets. RCCs and oncocytomas also exhibited an abundant immunoreactivity for Ln beta2 chain in both vessel and tumor cell BMs, while Ln alpha2 chain was not seen in any renal tumors. In distinction from RCCs, PRNs presented a strong BM immunoreactivity for Ln alpha3 and beta3 chains and for Ln-5, as well as lack of Ln beta2 chain. A more variable reactivity for Ln-5 was seen in oncocytomas. As PRNs and oncocytomas have been suggested to originate from collecting ducts, it is notable that in normal human kidney, we could detect immunoreactivity for Ln-5 and its chains only in BM of the tubules of the loop of Henle. In immunoprecipitation experiments, an abundant production of Ln-1, but not of Ln-5, was seen in cultured RCC cells, while in xenografts of the same cells BM-confined immunoreactivity for both Ln-1 and Ln-5 was seen. Ln beta2 chain was produced by 2 of the 4 RCC cell lines in culture but was found only in 1 of the xenografted tumors.
- Published
- 1996
- Full Text
- View/download PDF
200. A two-year dietary carcinogenicity study of the antiestrogen toremifene in Sprague-Dawley rats.
- Author
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Karlsson S, Hirsimäki Y, Mäntylä E, Nieminen L, Kangas L, Hirsimäki P, Perry CJ, Mulhern M, Millar P, Handa J, and Williams GM
- Subjects
- Aging drug effects, Animals, Antineoplastic Agents, Hormonal chemistry, Antineoplastic Agents, Hormonal metabolism, Body Weight drug effects, Carcinogenicity Tests, Eating drug effects, Female, Gonads drug effects, Liver pathology, Male, Neoplasms chemically induced, Precancerous Conditions chemically induced, Rats, Rats, Sprague-Dawley, Survival Rate, Toremifene chemistry, Toremifene metabolism, Antineoplastic Agents, Hormonal toxicity, Toremifene toxicity
- Abstract
The carcinogenic potential of the nonsteroidal triphenylethylene antiestrogen toremifene (Fareston) was evaluated in a standard 104-week rat dietary carcinogenicity study. The doses were 0, 0.12, 1.2, 5.0 and 12 mg/kg/day and the number of animals 50/sex/dose group. The body weight gain and food consumption were monitored once weekly (study weeks 1-16) or once every four weeks thereafter (study weeks 17-104). Blood samples were taken at weeks 34, 52 and 104 and the plasma concentrations of toremifene, as well as the two main metabolites (deaminohydroxy)toremifene and N-demethyltoremifene, were measured. All doses of toremifene reduced food intake and body weight gain. Toremifene caused a significant reduction in mortality, which was mainly due to reduced incidences of pituitary tumors. This was evident in all dose groups. Drug-related decrease of mammary tumors in females (at all doses) and testicular tumors in male rats (doses > or = 1.2 mg/kg/day) were also evident. The incidence of the preneoplastic foci of basophilic hepatocytes were significantly decreased in treated female groups. Toremifene induced no preneoplastic or neoplastic lesions. Based on histopathology, no obvious toxicity could be observed. Drug-related changes were observed in the genital organs, thyroid, spleen, mammary gland, adrenal, kidney, stomach and lung. These changes were due to hormonal disturbances or as a result of reduced food consumption or reduced incidences of pituitary, mammary or testicular tumors. This study indicates that toremifene is an efficient antiestrogen in long-term treatment, is well tolerated and has no tumorigenic potential in rats.
- Published
- 1996
- Full Text
- View/download PDF
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